BA1 is met: this variant has an allele frequency of 1.11% in gnomAD v4.1 (17,140/1,543,370 alleles, 139 homozygotes), exceeding the stand-alone benign threshold of >1%.1 BS1 is met: the variant is present at 0.722% in gnomAD v2.1 (1,232/170,616 alleles, 10 homozygotes), exceeding the strong benign threshold of >0.3%.2 BP3 is met: the variant is an in-frame duplication (p.Gln324_His325dup) within a repetitive low-complexity poly-QH tract in the SOX17 C-terminal region, consistent with a benign in-frame insertion in a repetitive region without known function. Under generic ACMG/AMP 2015 combination rules, BA1 alone is sufficient for a Benign classification. Independently, BS1 (strong benign) plus BP3 (supporting benign) also exceeds the Likely Benign threshold of one strong benign plus one supporting benign criterion.3 The variant is classified in ClinVar as Benign (2 clinical laboratories) and Likely benign (1 clinical laboratory) under Variation ID 915867, consistent with the population evidence.4
SOX17
Final classification
Benign
SOX17 c.972_977dup · p.Gln324_His325dup
SOX17
BA1 is met: this variant has an allele frequency of 1.11% in gnomAD v4.1 (17,140/1,543,370 alleles, 139 homozygotes), exceeding the stand-alone benign threshold of >1%.
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: BA1 stand-alone benign, BS1 strong benign, BP3 supporting benign; combination = 1 stand-alone benign + 1 strong benign + 1 supporting benign, which maps to Benign.
Classification rationale
BA1BS1BP3
Benign
SOX17 c.972_977dup
BA1 + BS1 + BP3
→
Benign
Gene diagram
· NM_022454.3 · variants mapped to exon structure
SOX17
NM_022454.3
Fetching transcript structure from UCSC…
Applied criteria · 3 applied · 21 assessed
Applied · 3
Strength
Supporting
Moderate
Strong
Very strong
✓
BA1
stand-alone
Benign
This variant is present at an allele frequency of 1.11% in gnomAD v4.1 (17,140/1,543,370 alleles, 139 homozygotes), exceeding the BA1 threshold of >1%. The highest subpopulation frequency is 1.32% in European (non-Finnish) (15,213/1,148,906 alleles, 122 homozygotes). The variant is too common to be a cause of a rare Mendelian disorder.
gnomAD v4.1: AF=1.11% (17140/1543
✓
BS1
strong
Benign
This variant is present at an allele frequency of 0.722% in gnomAD v2.1 (1,232/170,616 alleles, 10 homozygotes), exceeding the BS1 threshold of >0.3%. The highest subpopulation frequency is 1.21% in European (non-Finnish) (824/68,336 alleles, 7 homozygotes). The variant is more common than expected for a pathogenic variant causing a rare disorder.
gnomAD v2.1: AF=0.722% (1232/170616 alleles)
✓
BP3
supporting
Benign
NM_022454.3:c.972_977dup encodes an in-frame duplication of Gln324 and His325 (p.Gln324_His325dup), which reside within a repetitive low-complexity poly-QH tract in the C-terminal region of SOX17. The native sequence contains multiple QH dipeptide repeats (QMQPQHQHQHQHQHQHH...), and the duplication inserts an additional QH unit into this repetitive region. In-frame duplications within repetitive regions without known function are consistent with benign variation under BP3.
Protein context: p.Gln324_His325dup falls within repetitive poly-QH tract (QHQHQHQHQHQH...). The duplication adds one additional QH repeat unit to an already repetitive low-complexity region. No known critical function assigned to this region.
Assessed · not applied
Pathogenic
PVS1
NM_022454.3:c.972_977dup is an in-frame duplication (p.Gln324_His325dup) that does not qualify as a null variant under the ClinGen SVI PVS1 decision tree (PMC6185798).
PS2
No de novo occurrence data available for this variant.
PS3
No functional data exists for NM_022454.3:c.972_977dup or a systematically characterized range that includes this position.
PS4
This variant is common in the general population (gnomAD v4.1 AF = 1.11%, 139 homozygotes), inconsistent with a pathogenic variant enriched in affected individuals.
PM1
Position 324–325 resides in the C-terminal poly-QH repetitive region of SOX17, outside of the HMG-box DNA-binding domain (residues ~67–135).
PM2
This variant is common in population databases.
PM4
Although NM_022454.3:c.972_977dup is an in-frame duplication that alters protein length (p.Gln324_His325dup), it occurs within a repetitive low-complexity poly-QH region and is present at high frequency in the general population (gnomAD v4.1 AF = 1.11%, 139 homozygotes).
PM6
No de novo reports identified for NM_022454.3:c.972_977dup.
PP1
No segregation data available for this variant.
PP2
PP2 applies to missense variants in genes with a low rate of benign missense variation and where missense changes are a common disease mechanism.
PP3
In silico pathogenicity predictors (REVEL, BayesDel) are not available for duplication variants.
PP4
No patient phenotype or clinical data were provided for this case.
PP5
ClinVar classifies this variant as Benign (2 clinical laboratories) and Likely benign (1 clinical laboratory) with review status 'criteria provided, single submitter' (ClinVar Variation ID: 915867).
Benign
BS2
BS2 requires observation in a healthy adult individual for a disorder with full penetrance expected at an early age.
BS3
BS3 requires well-established in vitro or in vivo functional studies showing no damaging effect.
BS4
BS4 requires lack of segregation in affected family members.
BP1
BP1 applies to missense variants in genes where primarily truncating variants cause disease.
BP2
BP2 requires observation in trans with a pathogenic variant for a fully penetrant dominant disorder, or in cis with a pathogenic variant.
BP4
BP4 requires multiple lines of computational evidence suggesting no impact.
BP5
BP5 requires the variant to be found in a case with an alternate molecular basis for disease.
BP6
ClinVar classifies this variant as Benign/Likely benign with review status 'criteria provided, single submitter' (ClinVar Variation ID: 915867).
N/A · 4
PS1 · PM3 · PM5 · BP7
Research & evidence
Population frequency · supports benign
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 0.0111056; MAF= 1.11056%, 17140/1543370 alleles, homozygotes = 139) and has highest observed frequency in the European (non-Finnish) population (AF= 0.0132413; MAF= 1.32413%, 15213/1148906 alleles, homozygotes = 122); grpmax FAF= 0.0130646.
v2.1
This variant is present in gnomAD v2.1 (AF= 0.00722089; MAF= 0.72209%, 1232/170616 alleles, homozygotes = 10) and has highest observed frequency in the European (non-Finnish) population (AF= 0.0120581; MAF= 1.20581%, 824/68336 alleles, homozygotes = 7); grpmax FAF= 0.0118218.
🇨🇦 CA
This variant is present in gnomAD-Canada v1.0 (AF= 0.010005437737901033, 184/18390 alleles, homozygotes = 1).
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
1.1%
· 17140 / 1,543,370
139 hom · FAF 1.3%
139 hom · FAF 1.3%
European (non-Finnish) 15213 / 1,148,906 |
1.3% 122 hom |
Remaining individuals 605 / 60,150 |
1% 6 hom |
European (Finnish) 393 / 48,480 |
0.81% 2 hom |
South Asian 544 / 84,718 |
0.64% 7 hom |
Middle Eastern 27 / 5,996 |
0.45% 2 hom |
Amish 3 / 912 |
0.33% |
Admixed American 149 / 51,432 |
0.29% |
African/African American 142 / 73,180 |
0.19% |
Ashkenazi Jewish 43 / 28,636 |
0.15% |
East Asian 21 / 40,960 |
0.051% |
gnomAD v2.1
0.72%
· 1232 / 170,616
10 hom · FAF 1.2%
10 hom · FAF 1.2%
European (non-Finnish) 824 / 68,336 |
1.2% 7 hom |
Remaining individuals 61 / 5,274 |
1.2% 2 hom |
European (Finnish) 93 / 11,566 |
0.8% |
South Asian 131 / 23,210 |
0.56% 1 hom |
Admixed American 72 / 25,858 |
0.28% |
Ashkenazi Jewish 18 / 8,450 |
0.21% |
African/African American 25 / 15,520 |
0.16% |
East Asian 8 / 12,402 |
0.065% |
gnomAD Canada 🇨🇦
1%
· 184 / 18,390
1 hom · FAF 1.2%
1 hom · FAF 1.2%
indel · split
European (non-Finnish) 161 / 11,720 |
1.4% 1 hom |
Latino/Admixed American 6 / 838 |
0.72% |
Remaining individuals 7 / 1,138 |
0.62% |
South Asian 6 / 1,362 |
0.44% |
Ashkenazi Jewish 2 / 832 |
0.24% |
African/African American 1 / 1,012 |
0.099% |
East Asian 1 / 1,336 |
0.075% |
+ 2 not observed (European (Finnish), Middle Eastern)
ClinVar
This variant has been reported in ClinVar as Benign (2 clinical laboratories) and as Likely benign (1 clinical laboratory). (ClinVarID = 915867)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
Functional
Unknown Oncogenic Effect
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. SOX17 encodes a transcription factor involved in embryonic development and cell fate. Methylation and downregulation of SOX17 are found in colon, live
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV52026813, n = 3 times).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links
Triaged references · 2 PMIDs not cited in assessment
25741868 ↗
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.
CLINVAR
28492532 ↗
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
CLINVAR