NM_022454.3:c.972_977dup

SOX17 · NP_071899.1:p.(Gln324_His325dup) · NM_022454.3

GRCh37: chr8:55372258 A>ACACCAG · GRCh38: chr8:54459698 A>ACACCAG

Gene: SOX17 Transcript: NM_022454.3

Final call

Benign

BA1 stand-alone benign BS1 strong benign BP3 supporting benign

Variant details

Gene

SOX17

Transcript

NM_022454.3

Protein

NP_071899.1:p.(Gln324_His325dup)

gnomAD AF

0.01110556768629687 (v4.1)

ClinVar

Benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

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%.

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%.

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.

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.

Final determination: Generic ACMG/AMP 2015 fallback rules support a Benign classification because either BA1 is met or at least two strong benign criteria are present.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	Not met	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). It is not a nonsense, frameshift, or canonical ±1,2 splice site variant. No alternative PVS1 mechanism (e.g., initiation codon disruption, exon deletion) applies.	pvs1_generic_framework
PS1	N/A	PS1 requires a different nucleotide change at the same position producing the same amino acid change. This is a duplication variant, not a single nucleotide substitution.
PS2	Not met	No de novo occurrence data available for this variant. No publications report confirmed de novo observation of NM_022454.3:c.972_977dup with maternity and paternity confirmed.
PS3	Not met	No functional data exists for NM_022454.3:c.972_977dup or a systematically characterized range that includes this position. OncoKB classifies this variant as 'Unknown Oncogenic Effect' with no variant-specific functional evidence. No publications were identified that report experimental functional assays for this variant or for a tiling/saturation mutagenesis study covering residue 324–325.	oncokb
PS4	Not met	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. No case-control studies demonstrating enrichment in disease cohorts were identified.	gnomad_v2 gnomad_v4
PS5	N/A	PS5 requires a different nucleotide change at the same position yielding the same amino acid change with established pathogenicity. This is a duplication variant, not a nucleotide substitution.
PM1	Not met	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). This is not a well-characterized functional domain, and cancerhotspots.org does not identify a statistically significant hotspot at this residue. No literature defines a critical functional domain spanning positions 324–325.	oncokb
PM2	Not met	This variant is common in population databases. gnomAD v4.1 allele frequency is 1.11% (17,140/1,543,370 alleles, 139 homozygotes), far exceeding the PM2 threshold of <0.1%. The variant is also present in gnomAD v2.1 at 0.722% (1,232/170,616 alleles, 10 homozygotes).	gnomad_v2 gnomad_v4
PM3	N/A	Skipped per adjudication instructions — not assessed for this case.
PM4	Not met	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). The high population frequency and location in a repetitive region indicate this is a benign length polymorphism rather than a pathogenic protein length change.	gnomad_v2 gnomad_v4
PM5	N/A	PM5 requires a missense comparator at the same residue with established pathogenicity. This variant is a duplication (p.Gln324_His325dup), not a missense change. The automated PM5 candidate harvest could not identify eligible same-residue missense comparators.	pm5_candidates
PM6	Not met	No de novo reports identified for NM_022454.3:c.972_977dup. PM6 requires a confirmed de novo observation with both maternity and paternity confirmed. No publications or ClinVar submissions report de novo occurrence of this variant.
PP1	Not met	No segregation data available for this variant. No family studies or co-segregation analyses were identified in ClinVar submissions or the literature.
PP2	Not met	PP2 applies to missense variants in genes with a low rate of benign missense variation and where missense changes are a common disease mechanism. NM_022454.3:c.972_977dup is an in-frame duplication, not a missense variant. Additionally, SOX17 is not established as having a low rate of benign missense variation.
PP3	Not met	In silico pathogenicity predictors (REVEL, BayesDel) are not available for duplication variants. SpliceAI predicts no splice impact (max delta score = 0.00). No HCI prior probability score is available for SOX17. There are no multiple lines of computational evidence supporting a deleterious effect.	spliceai
PP4	Not met	No patient phenotype or clinical data were provided for this case. PP4 requires that the variant be identified in an individual with a phenotype and family history highly specific for the gene/disease. No such data are available.
PP5	Not met	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). PP5 requires a 3-star expert panel review for supporting-level application. The single-submitter review status does not meet this threshold. Furthermore, the ClinVar classification is benign, not pathogenic.	clinvar
BA1	Met	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
BS1	Met	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
BS2	Not met	BS2 requires observation in a healthy adult individual for a disorder with full penetrance expected at an early age. While multiple homozygotes (n=139) are observed in gnomAD v4.1, this constitutes population-level data rather than individual-level clinical confirmation of healthy adult status with expected disease phenotype absent. The gnomAD data are captured under BA1/BS1.
BS3	Not met	BS3 requires well-established in vitro or in vivo functional studies showing no damaging effect. No functional studies exist for NM_022454.3:c.972_977dup. OncoKB reports no variant-specific functional evidence. No publications were identified that experimentally assessed the functional consequence of this duplication.	oncokb
BS4	Not met	BS4 requires lack of segregation in affected family members. No family studies or segregation data are available for this variant.
BP1	Not met	BP1 applies to missense variants in genes where primarily truncating variants cause disease. NM_022454.3:c.972_977dup is an in-frame duplication, not a missense variant. Additionally, SOX17 has not been established as a gene where only truncating variants cause disease.
BP2	Not met	BP2 requires observation in trans with a pathogenic variant for a fully penetrant dominant disorder, or in cis with a pathogenic variant. No such data are available for this variant.
BP3	Met	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.	gnomad_v4
BP4	Not met	BP4 requires multiple lines of computational evidence suggesting no impact. For duplication variants, REVEL and BayesDel scores are not available. SpliceAI predicts no splice impact (max delta score = 0.00), but a single line of splicing evidence does not constitute 'multiple lines' under BP4. Insufficient computational evidence is available for this variant type to satisfy BP4.	spliceai
BP5	Not met	BP5 requires the variant to be found in a case with an alternate molecular basis for disease. No such data are available in the case materials.
BP6	Not met	ClinVar classifies this variant as Benign/Likely benign with review status 'criteria provided, single submitter' (ClinVar Variation ID: 915867). BP6 requires a 3-star expert panel review for supporting-benign application. The single-submitter status does not meet this threshold. The ClinVar benign classification is consistent with the population data but does not independently satisfy BP6 criteria.	clinvar
BP7	N/A	BP7 applies to synonymous (silent) variants with no predicted splice impact and low nucleotide conservation. NM_022454.3:c.972_977dup is an in-frame duplication, not a synonymous variant.

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