RUNX1 c.967+15A>G, p.?
NM_001754.4:c.967+15A>G
Variant of Uncertain Significance (VUS)
This intronic RUNX1 variant (c.967+15A>G) is rare and computationally predicted to have no splicing impact (BP4 applied). No additional pathogenic or benign criteria are met, resulting in a classification of Variant of Uncertain Significance.
ACMG/AMP Criteria Applied
BP4
Genetic Information
Gene & Transcript Details
Gene
RUNX1
Transcript
NM_001754.5
MANE Select
Total Exons
9
Strand
Reverse (−)
Reference Sequence
NC_000021.8
Alternative Transcripts
| ID | Status | Details |
|---|---|---|
| NM_001754.3 | Alternative | 8 exons | Reverse |
| NM_001754.4 | RefSeq Select | 9 exons | Reverse |
Variant Details
HGVS Notation
NM_001754.4:c.967+15A>G
Protein Change
?
Location
Exon 8
(Exon 8 of 9)
5'Exon Structure (9 total)3'
Functional Consequence
Loss of Function
Related Variants
Variant interpretation based on transcript NM_001754.5
Genome Browser
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HGVS InputNM_001754:c.967+15A>G
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Global Frequency
0.000398%
Extremely Rare
Highest in Population
European (non-Finnish)
0.000879%
Very Rare
Global: 0.000398%
European (non-Finnish): 0.000879%
0%
0.05%
0.1%
1%
5%
10%+
Allele Information
Total: 251474Alt: 1Homozygotes: 0
ACMG Criteria Applied
PM2
This variant is present in gnomAD (MAF= 0.000398%, 1/251474 alleles, homozygotes = 0) and at a higher frequency in the European (non-Finnish) population (MAF= 0.000879%, 1/113750 alleles, homozygotes = 0). The variant is rare (MAF < 0.1%), supporting PM2 criterion application.
Classification
Unknown (No data to parse)
Publications (0)
No publication details.
Clinical Statement
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: 0.78
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific) VCEP Guidelines
PVS1
PVS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PVS1 is: "Very Strong Per modified RUNX1 PVS1 decision tree for SNVs and CNVs and table of splicing effects. Modification Type: Gene-specific". The evidence for this variant shows: it is an intronic +15A>G change outside the canonical splice site and does not create a null effect. Therefore, this criterion is not applied because the variant does not meet the RUNX1-specific definition of a loss-of-function null variant.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS1 is: "Strong Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.". The evidence for this variant shows: no amino acid change is known or established. Therefore, this criterion is not applied because there is no identical amino acid change to a known pathogenic variant.
PS2
PS2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS2 (Moderate/Supporting) is based on de novo occurrence with confirmed maternity/paternity. The evidence for this variant shows: no reports of de novo occurrence. Therefore, this criterion is not applied because no de novo data are available.
PS3
PS3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS3 (Strong/Moderate/Supporting) is based on transactivation assays and secondary functional assays. The evidence for this variant shows: no functional studies have been performed. Therefore, this criterion is not applied due to lack of functional data.
PS4
PS4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS4 (Strong/Moderate/Supporting) is based on the number of probands meeting RUNX1-phenotypic criteria. The evidence for this variant shows: no probands have been reported. Therefore, this criterion is not applied because there are no case reports.
PM1
PM1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM1 is: "Moderate Variant affecting one of the following amino acid residues within the RHD...". The evidence for this variant shows: it is intronic and does not affect amino acid residues in the RHD. Therefore, this criterion is not applied.
PM2
PM2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM2 is: "Supporting Variant must be completely absent from all population databases.". The evidence for this variant shows: it is present in gnomAD at MAF=0.000398%. Therefore, this criterion is not applied because it is not completely absent.
PM3
PM3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM3 applies to recessive disorders observed in trans with a pathogenic variant. The evidence for this variant shows: no such observations. Therefore, this criterion is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM4 applies to in-frame deletions/insertions in the RHD. The evidence for this variant shows: it is a single-nucleotide intronic change. Therefore, this criterion is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM5 applies to missense changes at residues with known pathogenic variants. The evidence for this variant shows: no missense change is involved. Therefore, this criterion is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM6 is based on assumed de novo occurrences. The evidence for this variant shows: no de novo data. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP1 (Supporting/Moderate/Strong) is based on co-segregation data. The evidence for this variant shows: no family segregation data. Therefore, this criterion is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP2 applies to genes with low benign missense variation where missense variants are common disease mechanism. The evidence for this variant shows: it is intronic. Therefore, this criterion is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP3 is: "For synonymous and intronic variants: SpliceAI ≥ 0.38.". The evidence for this variant shows: SpliceAI=0.02. Therefore, this criterion is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP4 requires a highly specific phenotype. The evidence for this variant shows: no phenotype data. Therefore, this criterion is not applied.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP5 relies on reputable source assertions. The evidence for this variant shows: no such assertions are available. Therefore, this criterion is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BA1 is: "Stand Alone Minor allele frequency ≥ 0.15% in any general continental population.". The evidence for this variant shows: MAF=0.000398%. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS1 is: "Strong Minor allele frequency between 0.015% and 0.15% with ≥ 5 alleles observed.". The evidence for this variant shows: MAF=0.000398% but only 1 allele observed. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS2 applies when observed in healthy adults. The evidence for this variant shows: no such observations. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS3 is: "Strong Transactivation assays demonstrating normal function AND secondary assays.". The evidence for this variant shows: no functional assays. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS4 applies to lack of segregation in families. 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 applies to missense variants in genes where only truncating variants cause disease. The evidence for this variant shows: it is intronic. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP2 applies to observation in trans/cis with another pathogenic variant. The evidence for this variant shows: no such data. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP3 applies to in-frame indels in repetitive regions. The evidence for this variant shows: it is not an indel. Therefore, this criterion is not applied.
BP4
BP4 (Supporting)
According to VCEP guidelines, the rule for BP4 is: "For synonymous and intronic variants: SpliceAI ≤ 0.20.". The evidence for this variant shows: SpliceAI=0.02 indicating no significant splicing impact. Therefore, this criterion is applied at Supporting strength because computational evidence predicts no splicing effect.
BP5
BP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP5 applies when a variant is found in a case with an alternative molecular basis. The evidence for this variant shows: no alternative cause data. Therefore, this criterion is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP6 relies on a reputable source classifying the variant as benign. The evidence for this variant shows: no such classification. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP7 is: "Supporting BP7 is applicable for synonymous and intronic which SpliceAI ≤ 0.20 AND evolutionary conservation prediction algorithms predict the site as not conserved (phyloP100way ≤ 2.0).". The evidence for this variant shows: SpliceAI=0.02 but no conservation data available. Therefore, this criterion is not applied due to missing conservation information.