rs1555939564

Variant names:

• chr22-37983722-GCGGGGCTCCTCCGAGCCCA-G
• rs1555939564
• NM_006941.4:c.44_62delTGGGCTCGGAGGAGCCCCG

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_62delTGGGCTCGGAGGAGCCCCG​(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:3
• 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 rank	MANE	Protein	UniProt
SOX10	NM_006941.4	c.44_62delTGGGCTCGGAGGAGCCCCG	p.Val15AlafsTer11	frameshift_variant	Exon 2 of 4	ENST00000396884.8	NP_008872.1
POLR2F	NM_001301130.2	c.294-2423_294-2405delCTCCGAGCCCACGGGGCTC		intron_variant	Intron 4 of 5		NP_001288059.1
POLR2F	NM_001363825.1	c.*38+11421_*38+11439delCTCCGAGCCCACGGGGCTC		intron_variant	Intron 5 of 5		NP_001350754.1
POLR2F	NM_001301131.2	c.293+16561_293+16579delCTCCGAGCCCACGGGGCTC		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.44_62delTGGGCTCGGAGGAGCCCCG	p.Val15AlafsTer11	frameshift_variant	Exon 2 of 4	1	NM_006941.4	ENSP00000380093.2

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:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Waardenburg syndrome type 4C Pathogenic:1

-

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

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 -

not provided Pathogenic:1

Oct 04, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 27759048, 34599368, 29407415) -

Waardenburg syndrome type 2A Pathogenic:1

Mar 01, 2017

Laboratory of Human Genetics, Universidade de São Paulo

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

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;