rs397515367

Positions:

• chr22-37973817-GTC-G

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.1077_1078del​(p.Glu359AspfsTer42) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: SOX10 NM_006941.4 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 2.01

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 11 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 22-37973817-GTC-G is Pathogenic according to our data. Variant chr22-37973817-GTC-G is described in ClinVar as [Pathogenic]. Clinvar id is 7396.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr22-37973817-GTC-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SOX10	NM_006941.4	c.1077_1078del	p.Glu359AspfsTer42	frameshift_variant	4/4	ENST00000396884.8	NP_008872.1
POLR2F	NM_001301130.2	c.293+6651_293+6652del		intron_variant			NP_001288059.1
POLR2F	NM_001301131.2	c.293+6651_293+6652del		intron_variant			NP_001288060.1
POLR2F	NM_001363825.1	c.*38+1511_*38+1512del		intron_variant			NP_001350754.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SOX10	ENST00000396884.8	c.1077_1078del	p.Glu359AspfsTer42	frameshift_variant	4/4	1	NM_006941.4	ENSP00000380093	P1

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Waardenburg syndrome type 4C Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Feb 01, 1998

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 22, 2023

This variant disrupts a region of the SOX10 protein in which other variant(s) (p.Gln399Valfs*2) have been determined to be pathogenic (PMID: 23237859). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 7396). This variant is also known as 1076delGA. This premature translational stop signal has been observed in individual(s) with Waardenburg syndrome (PMID: 9462749). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Glu359Aspfs*42) in the SOX10 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 108 amino acid(s) of the SOX10 protein. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

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: rs397515367; hg19: chr22-38369824;