rs74315520

Variant names:

• chr22-37973767-G-A
• rs74315520
• NM_006941.4:c.1129C>T

Your query was ambiguous. Multiple possible variants found:

• chr22-37973767-G-A
• chr22-37973767-G-C

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_006941.4(SOX10):​c.1129C>T​(p.Gln377*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SOX10 NM_006941.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:3
• Conservation: PhyloP100: 9.59
• Publications: 6 publications found

Genes affected

SOX10 (HGNC:11190): (SRY-box transcription factor 10) This gene encodes a member of the SOX (SRY-related HMG-box) family of transcription factors involved in the regulation of embryonic development and in the determination of the cell fate. The encoded protein may act as a transcriptional activator after forming a protein complex with other proteins. This protein acts as a nucleocytoplasmic shuttle protein and is important for neural crest and peripheral nervous system development. Mutations in this gene are associated with Waardenburg-Shah and Waardenburg-Hirschsprung disease. [provided by RefSeq, Jul 2008]

POLR2F (HGNC:9193): (RNA polymerase II, I and III subunit F) This gene encodes the sixth largest subunit of RNA polymerase II, the polymerase responsible for synthesizing messenger RNA in eukaryotes. In yeast, this polymerase subunit, in combination with at least two other subunits, forms a structure that stabilizes the transcribing polymerase on the DNA template. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2014]

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 25 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 22-37973767-G-A is Pathogenic according to our data. Variant chr22-37973767-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 7402.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SOX10	NM_006941.4	c.1129C>T	p.Gln377*	stop_gained	Exon 4 of 4	ENST00000396884.8	NP_008872.1
POLR2F	NM_001301130.2	c.293+6597G>A		intron_variant	Intron 4 of 5		NP_001288059.1
POLR2F	NM_001363825.1	c.*38+1457G>A		intron_variant	Intron 5 of 5		NP_001350754.1
POLR2F	NM_001301131.2	c.293+6597G>A		intron_variant	Intron 4 of 4		NP_001288060.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SOX10	ENST00000396884.8	c.1129C>T	p.Gln377*	stop_gained	Exon 4 of 4	1	NM_006941.4	ENSP00000380093.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1444572 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 715868

African (AFR) AF: 0.00 AC: 0 AN: 32930

American (AMR) AF: 0.00 AC: 0 AN: 43290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25386

East Asian (EAS) AF: 0.00 AC: 0 AN: 39372

South Asian (SAS) AF: 0.00 AC: 0 AN: 84924

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52394

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5678

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1101132

Other (OTH) AF: 0.00 AC: 0 AN: 59466

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, single submitter

Submissions by phenotype

Waardenburg syndrome type 4C Pathogenic:1

Mar 01, 1999

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided Pathogenic:1

May 12, 2025

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported in two siblings with Waardenburg spectrum disorder and additional neurological abnormalities in the published literature (PMID: 10077527); Published functional studies demonstrate a damaging effect on SOX10 function in certain transcriptional pathways and mouse models show an abnormal phenotype compared to wildtype (PMID: 14523991, 16921166, 29361054); Nonsense variant predicted to result in protein truncation, as the last 90 amino acids are lost, and other loss-of-function variants have been reported downstream; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 19764030, 14523991, 16921166, 29361054, 22963253, 10077527) -

Waardenburg syndrome type 2E, with neurologic involvement Pathogenic:1

Mar 01, 1999

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.65
CADD	Pathogenic	40
DANN	Uncertain	1.0
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.98
FATHMM_MKL	Pathogenic	1.0	D
PhyloP100		9.6
Vest4		0.82
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=1/199	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs74315520; hg19: chr22-38369774;