rs74315520

Positions:

• chr22-37973767-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_Strong 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

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

Verdict is Likely_pathogenic. Variant got 8 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 4 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 id is 7402.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr22-37973767-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

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

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SOX10	ENST00000396884.8	c.1129C>T	p.Gln377*	stop_gained	4/4	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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, single submitter

Submissions by phenotype

Waardenburg syndrome type 4C Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 01, 1999

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jan 14, 2019

The Q377X nonsense variant in the SOX10 gene has been reported previously in individuals with Waardenburg syndrome type 4 and additional neurological abnormalities (Southard-Smith et al., 1999). It has also been reported as an apparently de novo variant in an individual with PCWH syndrome (Oshimo et al., 2012). This variant is predicted to cause loss of normal protein function through protein truncation, as the last 90 amino acids are lost, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (Stenson et al., 2014). Published functional studies demonstrate a damaging effect on SOX10 function in certain transcriptional pathways (Chan et al., 2003; Yokoyama et al., 2006), and mouse models show an abnormal phenotype compared to wild-type mice (Truch et al., 2018). The Q377X variant is not observed in large population cohorts (Lek et al., 2016). In summary, we interpret this variant as pathogenic. -

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

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 01, 1999

- -

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
Vest4		0.82
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

Publications

LitVar

Other links and lift over

dbSNP: rs74315520; hg19: chr22-38369774;