EXT1 c.1431C>T, p.Pro477=
NM_000127.3:c.1431C>T
COSMIC ID: COSM10647152
Likely Benign
This synonymous EXT1 variant is common in population databases (BA1, BS1, BS2), lacks any predicted functional or splicing impact (BP4, BP7), and is reported as benign by reputable sources (BP6), supporting a final classification of Benign.
ACMG/AMP Criteria Applied
BA1
BS1
BS2
BP4
BP6
BP7
Genetic Information
Gene & Transcript Details
Gene
EXT1
Transcript
NM_000127.3
MANE Select
Total Exons
11
Strand
Reverse (−)
Reference Sequence
NC_000008.10
Alternative Transcripts
| ID | Status | Details |
|---|---|---|
| NM_000127.2 | RefSeq Select | 11 exons | Reverse |
Variant Details
HGVS Notation
NM_000127.3:c.1431C>T
Protein Change
P477=
Location
Exon 6
(Exon 6 of 11)
5'Exon Structure (11 total)3'
Functional Consequence
Loss of Function
Related Variants
Alternate Identifiers
COSM10647152
Variant interpretation based on transcript NM_000127.3
Genome Browser
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HGVS InputNM_000127:c.1431C>T
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Global Frequency
17.8%
Common
Highest in Population
European (Finnish)
30.6%
Common
Global: 17.8%
European (Finnish): 30.6%
0%
0.05%
0.1%
1%
5%
10%+
Allele Information
Total: 282086Alt: 50153Homozygotes: 5100
ACMG Criteria Applied
BA1
This variant is present in gnomAD (MAF= 17.8%, 50153/282086 alleles, homozygotes = 5100) and at a higher frequency in the European (Finnish) population (MAF= 30.6%, 7678/25112 alleles, homozygotes = 1167). The variant is common (MAF > 1%), supporting BA1 criterion application.
Classification
Benign
Based on 5 submitter reviews in ClinVar
Submitter Breakdown
5 B
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (0)
No publication details.
Clinical Statement
This variant has been reported in ClinVar as Benign (5 clinical laboratories).
Functional Impact
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
Computational Analysis
Pathogenicity Predictions
Predictor Consensus
Mixed/VUS
PP3 Applied
No
Additional Predictors
Benign:
CADD: 0.63
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
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 synonymous variant (no change to protein). Therefore, this criterion is not applied 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: it is synonymous, no amino acid change. Therefore, this criterion is not applied because there is no 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 information on de novo status. Therefore, this criterion is not applied due to lack of de novo evidence.
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 because functional evidence is 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 disease prevalence data. Therefore, this criterion is not applied due to absence of case data.
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: it is a synonymous change outside known functional domains. Therefore, this criterion is not applied.
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: MAF=17.8% in gnomAD with 5100 homozygotes. Therefore, this criterion is not applied because the variant is common in controls.
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 data on observation in trans with a pathogenic variant. Therefore, this criterion is not applied due to lack of trans observation data.
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: it is synonymous with no protein length change. Therefore, this criterion is not applied.
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: it is synonymous. Therefore, this criterion is not applied.
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 assessment data. Therefore, this criterion is not applied due to lack of de novo information.
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 available. Therefore, this criterion is not applied.
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: it is synonymous. Therefore, this criterion is not applied.
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/gene product." The evidence for this variant shows: in silico predictors and SpliceAI predict no impact. Therefore, this criterion is not applied.
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 data provided. Therefore, this criterion is not applied.
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: reputable sources report it as benign. Therefore, this criterion is not applied.
BA1
BA1 (Stand Alone) Strength Modified
According to standard ACMG guidelines the rule for BA1 is: "Allele frequency is too high for the disorder." The evidence for this variant shows: MAF=17.8% in gnomAD with 5100 homozygotes. Therefore, this criterion is applied at Stand Alone strength.
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: MAF=17.8% which is well above disease prevalence thresholds. Therefore, this criterion is applied at Strong strength.
BS2
BS2 (Strong)
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: 5100 homozygotes in gnomAD presumed healthy. Therefore, this criterion is applied at Strong strength.
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.
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 segregation data. Therefore, this criterion is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines the rule for BP1 is: "Missense variant in a gene where only LoF causes disease." The evidence for this variant shows: it is synonymous. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines the rule for BP2 is: "Observed in trans with a pathogenic variant for dominant disorders or in cis with a pathogenic variant." The evidence for this variant shows: no data on cis/trans observations. Therefore, this criterion is not applied.
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: it is synonymous, not an indel. Therefore, this criterion is not applied.
BP4
BP4 (Supporting)
According to standard ACMG guidelines the rule for BP4 is: "Multiple lines of computational evidence suggest no impact." The evidence for this variant shows: in silico predictors (CADD=0.63) and SpliceAI predict no impact on splicing. Therefore, this criterion is applied at Supporting strength.
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 case reports with alternate molecular diagnosis. Therefore, this criterion is not applied.
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 by 5 laboratories without primary evidence. Therefore, this criterion is applied at Supporting strength.
BP7
BP7 (Supporting)
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 synonymous and SpliceAI scores are zero. Therefore, this criterion is applied at Supporting strength.