rs1555939564

Positions:

• chr22-37983722-GCGGGGCTCCTCCGAGCCCA-G

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_006941.4(SOX10):​c.44_62del​(p.Val15AlafsTer11) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SOX10 NM_006941.4 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 7.03

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 Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 83 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 22-37983722-GCGGGGCTCCTCCGAGCCCA-G is Pathogenic according to our data. Variant chr22-37983722-GCGGGGCTCCTCCGAGCCCA-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 488044.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-37983722-GCGGGGCTCCTCCGAGCCCA-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SOX10	NM_006941.4	c.44_62del	p.Val15AlafsTer11	frameshift_variant	2/4	ENST00000396884.8	NP_008872.1
POLR2F	NM_001301130.2	c.294-2423_294-2405del		intron_variant			NP_001288059.1
POLR2F	NM_001301131.2	c.293+16561_293+16579del		intron_variant			NP_001288060.1
POLR2F	NM_001363825.1	c.*38+11421_*38+11439del		intron_variant			NP_001350754.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SOX10	ENST00000396884.8	c.44_62del	p.Val15AlafsTer11	frameshift_variant	2/4	1	NM_006941.4	ENSP00000380093	P1

Frequencies

GnomAD3 genomes Cov.: 32

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

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Waardenburg syndrome type 4C Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Otorhinolaryngology Lab - LIM32, University of Sao Paulo School of Medicine Clinics Hospital

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Both parents with hearing loss, not inherited from the mother, father unavailable. Proband with bilateral profound sensorineural hearing loss, total iris heterochromia, and skin hypochromic spots, semicircular canals (mainly posterior) dysplasia with a fusion of its crus and absence of the corresponding bony islet, vestibule with slightly decreased dimensions with irregular morphology, Separation of the lateral aspect of the basal cochlea loop concerning the lateral aspect of the middle loop (unwound cochlea), suspicion of intestinal obstruction at birth -

Waardenburg syndrome type 2A Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Laboratory of Human Genetics, Universidade de São Paulo

Mar 01, 2017

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1555939564; hg19: chr22-38379729;