NM_001754.4:c.714C>A is a synonymous variant (p.Val238=) in exon 7 of RUNX1 that is absent from all population databases (gnomAD v2.1, v4.1).1 SpliceAI predicts a strong cryptic splice donor gain (DS_DG=0.96), meeting the VCEP PP3 threshold of ≥0.38 for synonymous variants, suggesting a potential splicing impact.2 PM2_Supporting is met: the variant is absent from gnomAD (MAF=0), meeting the VCEP threshold of ≤0.00005.3 PVS1 is not met: this is a synonymous variant, not a null variant; predicted splicing effects without RNA confirmation route to PP3 under the RUNX1 VCEP.4 PM1 is not met: codon 238 lies outside the Runt homology domain (AA 89-204), the critical functional domain specified by the VCEP.5 No functional studies, de novo data, proband counts, co-segregation evidence, or literature reports are available for this variant. Applying the point-based scoring system (Tavtigian 2020), PM2_Supporting contributes +1 point and PP3 contributes +1 point, for a total of 2 pathogenic points. The variant falls within the 0-5 point range and is classified as a Variant of Uncertain Significance (VUS).6
RUNX1
Final classification
VUS
RUNX1 c.714C>A · p.Val238=
RUNX1
NM_001754.4:c.714C>A is a synonymous variant (p.Val238=) in exon 7 of RUNX1 that is absent from all population databases (gnomAD v2.1, v4.1).
ClinGen Myeloid Malignancy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RUNX1 Version 3.1 v3.1 point-based framework: PM2 supporting (+1) + PP3 supporting (+1) = 2 points, which maps to VUS.
Classification rationale
PM2PP3
VUS
RUNX1 c.714C>A
PM2 + PP3
→
VUS
5
cspec ↗
6
final_classification_framework
Gene diagram
· NM_001754.4 · variants mapped to exon structure
RUNX1
NM_001754.4
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 14 assessed
Applied · 2
Strength
Supporting
Moderate
Strong
Very strong
✓
PM2
supporting
Pathogenic
This variant is absent from gnomAD v2.1 and v4.1 across all populations, meeting the VCEP PM2_Supporting threshold (MAF ≤ 0.00005 with ≥2,000 alleles tested and ≥20x coverage).
Absent from gnomAD v2.1 (exomes)Absent from gnomAD v4.1 (exomes)Absent from gnomAD-Canada v1.0
✓
PP3
supporting
Pathogenic
This synonymous variant has a SpliceAI donor gain delta score of 0.96, which exceeds the VCEP PP3 threshold of ≥0.38 for synonymous variants, indicating creation of a cryptic novel splice donor site. This variant is not at a canonical splice site and no RNA confirmation data is available.
SpliceAI DS_DG = 0.96 (donor gain)DS_DL = 0.79 (donor loss)Meets VCEP PP3 threshold for synonymous variants: SpliceAI ≥ 0.38
Assessed · not applied
Pathogenic
PVS1
NM_001754.4:c.714C>A is a synonymous variant (p.Val238=) and does not fall into the PVS1 null-variant buckets (nonsense, frameshift, or canonical splice consensus).
PS2
No de novo occurrence data (with confirmed maternity and paternity) is available for this variant in the FPD/AML phenotype.
PS3
No in vitro or in vivo functional studies have been reported for this synonymous variant.
PS4
This variant has not been reported in any probands meeting RUNX1-phenotypic criteria.
PM1
This synonymous variant affects codon 238 (p.Val238=), which lies outside the RUNX1 Runt homology domain (RHD; AA 89-204).
PM6
No assumed de novo occurrences have been reported for this variant in patients with FPD/AML phenotype.
PP1
No co-segregation data with disease in multiple affected family members is available for this variant.
Benign
BA1
This variant is absent from gnomAD.
BS1
This variant is absent from gnomAD.
BS3
No functional studies demonstrating normal transactivation (80-115% of wildtype) or normal function in secondary assays are available for this variant.
BS4
No segregation data is available to demonstrate lack of segregation in ≥2 informative meioses.
BP2
No evidence is available that this variant has been observed in trans with a known pathogenic variant or in cis with a pathogenic variant in any inheritance pattern.
BP4
The VCEP BP4 rule for synonymous variants requires SpliceAI ≤ 0.20.
BP7
The VCEP BP7 rule for synonymous variants requires SpliceAI Δ scores ≤ 0.20 and exclusion from the last 3 nucleotides preceding a canonical donor splice site or first nucleotide following a canonical acceptor splice site.
N/A · 9
PS1 · PM5 · PP2 · PP4 · PP5 · BS2 · BP1 · BP5 · BP6
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
Absent from gnomAD v4.1.
v2.1
Absent from gnomAD v2.1.
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
In silico
SpliceAI predicts possible splice impact for this variant (max delta score = 0.96).
Functional
Unknown Oncogenic Effect
OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links