chr22-37973566-GGCTGGGGTCAGAGAT-G

Position:

• chr22-37973566-GGCTGGGGTCAGAGAT-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PM4 PP3 PP5

The NM_006941.4(SOX10):​c.1315_1329del​(p.Ile439_Ser443del) variant causes a inframe deletion change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: SOX10 NM_006941.4 inframe_deletion
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 9.60

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 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_006941.4.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• PP5: Variant 22-37973566-GGCTGGGGTCAGAGAT-G is Pathogenic according to our data. Variant chr22-37973566-GGCTGGGGTCAGAGAT-G is described in ClinVar as [Pathogenic]. Clinvar id is 620636.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SOX10	NM_006941.4	c.1315_1329del	p.Ile439_Ser443del	inframe_deletion	4/4	ENST00000396884.8	NP_008872.1
POLR2F	NM_001301130.2	c.293+6398_293+6412del		intron_variant			NP_001288059.1
POLR2F	NM_001301131.2	c.293+6398_293+6412del		intron_variant			NP_001288060.1
POLR2F	NM_001363825.1	c.*38+1258_*38+1272del		intron_variant			NP_001350754.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SOX10	ENST00000396884.8	c.1315_1329del	p.Ile439_Ser443del	inframe_deletion	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:1

Revision: no assertion criteria provided

Submissions by phenotype

Waardenburg syndrome type 4A Pathogenic:1

Pathogenic, no assertion criteria provided

research

Hereditary Hearing Loss Research Unit, University of Madras

Mar 07, 2018

- -

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: rs1569167515; hg19: chr22-38369573;