rs483353057

Variant names:

• chr22-37983509-CACGGG-C
• rs483353057
• NM_006941.4:c.271_275delCCCGT

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_006941.4(SOX10):​c.271_275delCCCGT​(p.Pro91AlafsTer41) variant causes a frameshift 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 Likely pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SOX10 NM_006941.4 frameshift
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.47
• Publications: 1 publications found

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

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 22-37983509-CACGGG-C is Pathogenic according to our data. Variant chr22-37983509-CACGGG-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 133303.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006941.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SOX10	NM_006941.4	MANE Select	c.271_275delCCCGT	p.Pro91AlafsTer41	frameshift	Exon 2 of 4	NP_008872.1	P56693-1
	POLR2F	NM_001301130.2		c.294-2644_294-2640delACGGG		intron	N/A	NP_001288059.1	B0QYL9
	POLR2F	NM_001363825.1		c.*38+11200_*38+11204delACGGG		intron	N/A	NP_001350754.1	F8WC47

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SOX10	ENST00000396884.8	TSL:1 MANE Select	c.271_275delCCCGT	p.Pro91AlafsTer41	frameshift	Exon 2 of 4	ENSP00000380093.2	P56693-1
	SOX10	ENST00000360880.6	TSL:1	c.271_275delCCCGT	p.Pro91AlafsTer41	frameshift	Exon 3 of 5	ENSP00000354130.2	P56693-1
	SOX10	ENST00000698177.1		c.487_491delCCCGT	p.Pro163AlafsTer41	frameshift	Exon 3 of 5	ENSP00000513596.1	A0A8V8TM01

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

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Waardenburg syndrome type 4C (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.5
Mutation Taster		=1/199	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs483353057; hg19: chr22-38379516;