rs397515366

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PM4PP3PP5

The NM_006941.4(SOX10):​c.482_483insGCTCCT​(p.Arg161_Met162insLeuLeu) variant causes a disruptive inframe insertion 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: 32)

Consequence

SOX10
NM_006941.4 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 7.90
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PM1
In a region_of_interest Disordered (size 39) in uniprot entity SOX10_HUMAN there are 13 pathogenic changes around while only 0 benign (100%) in NM_006941.4
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 22-37978081-A-AAGGAGC is Pathogenic according to our data. Variant chr22-37978081-A-AAGGAGC is described in ClinVar as [Pathogenic]. Clinvar id is 7395.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
SOX10NM_006941.4 linkuse as main transcriptc.482_483insGCTCCT p.Arg161_Met162insLeuLeu disruptive_inframe_insertion 3/4 ENST00000396884.8 NP_008872.1 P56693-1A0A024R1N6
POLR2FNM_001301130.2 linkuse as main transcriptc.294-8073_294-8072insAGGAGC intron_variant NP_001288059.1 B0QYL9
POLR2FNM_001363825.1 linkuse as main transcriptc.*38+5771_*38+5772insAGGAGC intron_variant NP_001350754.1
POLR2FNM_001301131.2 linkuse as main transcriptc.293+10911_293+10912insAGGAGC intron_variant NP_001288060.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
SOX10ENST00000396884.8 linkuse as main transcriptc.482_483insGCTCCT p.Arg161_Met162insLeuLeu disruptive_inframe_insertion 3/41 NM_006941.4 ENSP00000380093.2 P56693-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: no assertion criteria provided
LINK: link

Submissions by phenotype

Waardenburg syndrome type 4C Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyOMIMFeb 01, 1998- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs397515366; hg19: chr22-38374088; API