22-37973484-CAGGGCCCCCTTT-C

Position:

• chr22-37973484-CAGGGCCCCCTTT-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_006941.4(SOX10):​c.1400_*10del variant causes a stop lost, 3 prime UTR 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: 33)
• Consequence: SOX10 NM_006941.4 stop_lost, 3_prime_UTR
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 3.66

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 12 ACMG points.

• PVS1: Stoplost variant. No alternative stopcodon identified downstream, so we assume a Nonstop Mediated Decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 22-37973484-CAGGGCCCCCTTT-C is Pathogenic according to our data. Variant chr22-37973484-CAGGGCCCCCTTT-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 7400.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr22-37973484-CAGGGCCCCCTTT-C is described in Lovd as [Pathogenic]. Variant chr22-37973484-CAGGGCCCCCTTT-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SOX10	NM_006941.4	c.1400_*10del		stop_lost, 3_prime_UTR_variant	4/4	ENST00000396884.8
POLR2F	NM_001301130.2	c.293+6321_293+6332del		intron_variant
POLR2F	NM_001301131.2	c.293+6321_293+6332del		intron_variant
POLR2F	NM_001363825.1	c.*38+1181_*38+1192del		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SOX10	ENST00000396884.8	c.1400_*10del		stop_lost, 3_prime_UTR_variant	4/4	1	NM_006941.4	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: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

PCWH syndrome Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 15, 2007	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	3billion	Mar 22, 2022	This loss of stop variant can change the length of the protein and disrupt protein function. This variant has been reported as pathogenic (ClinVar ID: VCV000007400, PMID:10482261).It is not observed in the gnomAD v2.1.1 dataset. Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline. -

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: rs397515368; hg19: chr22-38369491;