RNF43 c.1093G>A, p.Ala365Thr
NM_017763.6:c.1093G>A
COSM6352048
Population Frequency
0.35%
Common
ClinVar Classification
Benign
0 publications
REVEL Score
0.003
Likely Benign
COSMIC Recurrence
4 occurrences
No Criteria Applied
Classification Evidence
Detailed Information
Genetic Information
Gene & Transcript Details
Gene
RNF43
Transcript
NM_017763.6
MANE Select
Total Exons
10
Strand
Reverse (−)
Reference Sequence
NC_000017.10
Alternative Transcripts
| ID | Status | Details |
|---|---|---|
| NM_017763.4 | Alternative | 10 exons | Reverse |
| NM_017763.3 | Alternative | 9 exons | Reverse |
| NM_017763.5 | RefSeq Select | 10 exons | Reverse |
Variant Details
HGVS Notation
NM_017763.6:c.1093G>A
Protein Change
A365T
Location
Exon 9
(Exon 9 of 10)
5'
Exon Structure (10 total)
3'
Functional Consequence
Loss of Function
Related Variants
No evidence of other pathogenic variants at position 365 in gene RNF43
Alternate Identifiers
COSM6352048
Variant interpretation based on transcript NM_017763.6
Clinical Evidence
Global Frequency
0.35%
Common
Highest in Population
East Asian
3.56%
Common
Global: 0.35%
East Asian: 3.56%
0%
0.0005%
0.001%
0.01%
0.05%
1%+
Allele Information
Total: 168116
Alt: 588
Homozygotes: 8
ACMG Criteria Applied
BS1
This variant is present in gnomAD (MAF= 0.35%, 588/168116 alleles, homozygotes = 8) and at a higher frequency in the East Asian population (MAF= 3.56%, 478/13414 alleles, homozygotes = 5). The variant frequency (0.3% <= MAF <= 1%) supports BS1 criterion application.
Classification
Benign
Based on 5 submitter reviews in ClinVar
Submitter Breakdown
Pathogenic
Likely Pathogenic
VUS
Likely Benign
Benign
Publications
0 publications
Clinical Statement
This variant has been reported in ClinVar as Benign (5 clinical laboratories).
Functional Domain
Hotspot Status
Not a hotspot
Domain Summary
This variant is not located in a mutational hotspot or critical domain (0 mutations).
Related Variants in This Domain
No evidence of other pathogenic variants at position 365 in gene RNF43
Functional Studies
Summary
The RNF43 A365T variant has not been functionally characterized, and its biological significance remains unknown.
Computational Evidence
Pathogenicity Predictions
REVEL Score
0.003
0.003
Likely Benign
0.0
Uncertain (Low)
0.2
Uncertain (Med)
0.5
Likely Pathogenic
0.75
REVEL scores ≥ 0.75 are considered strong evidence of pathogenicity (PP3)
Predictor Consensus
Mixed/VUS
PP3 Applied
No
Additional Predictors
Benign:
CADD: -0.69
polyphen_prediction: benign
metasvm: T
metalr: T
primateai: T
Neutral:
Show all
VCEP Guidelines
Applied ACMG/AMP Criteria
PVS1
PVS1 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PVS1 is: 'Null variant in a gene where loss of function (LoF) is a known mechanism of disease.' The evidence for this variant shows: it is a missense change (c.1093G>A, p.A365T), not a null variant. Therefore, this criterion is not applied at Not Applied strength because the variant is not a null variant.
PS1
PS1 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PS1 is: 'Same amino acid change as a known pathogenic variant but different nucleotide change.' The evidence for this variant shows: no known pathogenic variant results in the same amino acid change at residue 365. Therefore, this criterion is not applied at Not Applied strength because there is no pathogenic variant with the same amino acid change.
PS2
PS2 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PS2 is: 'De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.' The evidence for this variant shows: no de novo data available. Therefore, this criterion is not applied at Not Applied strength because de novo status is unconfirmed.
PS3
PS3 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PS3 is: 'Well-established functional studies supportive of a damaging effect on the gene or gene product.' The evidence for this variant shows: no functional studies have been performed. Therefore, this criterion is not applied at Not Applied strength because functional data are lacking.
PS4
PS4 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PS4 is: 'Prevalence in affected individuals significantly increased compared with controls.' The evidence for this variant shows: no case–control or affected individual prevalence data. Therefore, this criterion is not applied at Not Applied strength because case prevalence data are unavailable.
PM1
PM1 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PM1 is: 'Located in a mutational hot spot or well-established functional domain without benign variation.' The evidence for this variant shows: residue A365 is not within a known mutational hotspot or critical functional domain. Therefore, this criterion is not applied at Not Applied strength because the variant is not in a defined hotspot or domain.
PM2
PM2 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PM2 is: 'Absent from controls (or at extremely low frequency if recessive).' The evidence for this variant shows: present in gnomAD at MAF=0.35% (588/168116 alleles) including homozygotes. Therefore, this criterion is not applied at Not Applied strength because the variant is not absent or at extremely low frequency.
PM3
PM3 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PM3 is: 'Detected in trans with a pathogenic variant (for recessive disorders).' The evidence for this variant shows: no trans data available. Therefore, this criterion is not applied at Not Applied strength because trans configuration with a pathogenic variant is unknown.
PM4
PM4 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PM4 is: 'Protein length changes due to in-frame deletions/insertions or stop-loss variants.' The evidence for this variant shows: a single amino acid substitution without length change. Therefore, this criterion is not applied at Not Applied strength because there is no protein length alteration.
PM5
PM5 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PM5 is: 'Novel missense change at an amino acid residue where a different pathogenic missense change has been seen.' The evidence for this variant shows: no other pathogenic missense changes reported at residue A365. Therefore, this criterion is not applied at Not Applied strength because no pathogenic variant exists at the same residue.
PM6
PM6 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PM6 is: 'Assumed de novo, but without confirmation of paternity and maternity.' The evidence for this variant shows: no de novo or parental testing information. Therefore, this criterion is not applied at Not Applied strength because de novo status is unconfirmed.
PP1
PP1 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PP1 is: 'Co-segregation with disease in multiple affected family members.' The evidence for this variant shows: no segregation data reported. Therefore, this criterion is not applied at Not Applied strength because family segregation data are lacking.
PP2
PP2 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PP2 is: 'Missense variant in a gene with a low rate of benign missense variation and where missense variants are a common mechanism of disease.' The evidence for this variant shows: RNF43 has not been established as a gene where missense is the primary disease mechanism. Therefore, this criterion is not applied at Not Applied strength because the gene-specific missense context is not met.
PP3
PP3 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PP3 is: 'Multiple lines of computational evidence support a deleterious effect on the gene or gene product.' The evidence for this variant shows: computational tools (REVEL=0.00, CADD, PolyPhen, SpliceAI) predict no deleterious effect. Therefore, this criterion is not applied at Not Applied strength because in silico evidence does not support a deleterious effect.
PP4
PP4 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PP4 is: 'Patient's phenotype or family history highly specific for a disease with a single genetic etiology.' The evidence for this variant shows: no phenotype or family history information provided. Therefore, this criterion is not applied at Not Applied strength due to lack of phenotypic specificity data.
PP5
PP5 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PP5 is: 'Reputable source reports variant as pathogenic, but without accessible evidence.' The evidence for this variant shows: no reputable source reports it as pathogenic. Therefore, this criterion is not applied at Not Applied strength because no source claims pathogenicity.
BA1
BA1 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for BA1 is: 'Allele frequency is too high for the disorder (based on population data).' The evidence for this variant shows: MAF=0.35% which is below typical BA1 thresholds (~5%). Therefore, this criterion is not applied at Not Applied strength because allele frequency does not exceed BA1 threshold.
BS1
BS1 (Strong)
According to standard ACMG guidelines, the rule for BS1 is: 'Allele frequency is greater than expected for the disorder.' The evidence for this variant shows: present at MAF=0.35% overall and up to 3.56% in East Asians, exceeding expected frequency for a dominant disease. Therefore, this criterion is applied at Strong strength because the population frequency is greater than expected for a pathogenic variant.
BS2
BS2 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for BS2 is: 'Observed in healthy individuals with full penetrance expected at an early age.' The evidence for this variant shows: observed homozygotes in population databases but no information on clinical follow-up. Therefore, this criterion is not applied at Not Applied strength because absence of confirmed healthy adult data limits full confidence.
BS3
BS3 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for BS3 is: 'Well-established functional studies show no damaging effect on protein function or splicing.' The evidence for this variant shows: no functional studies available. Therefore, this criterion is not applied at Not Applied strength because functional assay data are lacking.
BS4
BS4 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for BS4 is: 'Lack of segregation in affected family members.' The evidence for this variant shows: no familial segregation information. Therefore, this criterion is not applied at Not Applied strength because segregation data are unavailable.
BP1
BP1 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for BP1 is: 'Missense variant in a gene where only loss-of-function causes disease.' The evidence for this variant shows: RNF43 disease association is not strictly limited to LoF, and missense effects are not definitively benign. Therefore, this criterion is not applied at Not Applied strength due to uncertainty about mechanistic specificity.
BP2
BP2 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for BP2 is: 'Observed in trans with a pathogenic variant for a dominant disorder or in cis with a pathogenic variant.' The evidence for this variant shows: no data on cis/trans with other variants. Therefore, this criterion is not applied at Not Applied strength due to lack of phasing data.
BP3
BP3 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for BP3 is: 'In-frame deletions/insertions in a repetitive region without known function.' The evidence for this variant shows: not an in-frame indel and not in a repetitive region. Therefore, this criterion is not applied at Not Applied strength because the variant type does not match BP3.
BP4
BP4 (Supporting)
According to standard ACMG guidelines, the rule for BP4 is: 'Multiple lines of computational evidence suggest no impact on gene or gene product.' The evidence for this variant shows: REVEL=0.00, benign CADD and PolyPhen scores, and no splicing impact by SpliceAI. Therefore, this criterion is applied at Supporting strength because multiple in silico tools predict a benign effect.
BP5
BP5 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for BP5 is: 'Variant found in a case with an alternate molecular basis for disease.' The evidence for this variant shows: no such case reports. Therefore, this criterion is not applied at Not Applied strength due to absence of case data.
BP6
BP6 (Supporting)
According to standard ACMG guidelines, the rule for BP6 is: 'Reputable source reports variant as benign, but without accessible evidence.' The evidence for this variant shows: ClinVar reports it as Benign (5 laboratories) without primary evidence available. Therefore, this criterion is applied at Supporting strength because a reputable database classifies it as benign.
BP7
BP7 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for BP7 is: 'Synonymous variant with no predicted impact on splicing.' The evidence for this variant shows: it is a missense variant, not synonymous. Therefore, this criterion is not applied at Not Applied strength because the variant is not synonymous.