rs1555939415
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1PM2PM5PP3_StrongPP5_Moderate
The NM_006941.4(SOX10):c.403A>G(p.Ser135Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S135T) has been classified as Pathogenic.
Frequency
Genomes: not found (cov: 32)
Consequence
SOX10
NM_006941.4 missense
NM_006941.4 missense
Scores
9
9
1
Clinical Significance
Conservation
PhyloP100: 4.99
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 Pathogenic. Variant got 12 ACMG points.
PM1
In a short_sequence_motif Nuclear export signal (size 11) in uniprot entity SOX10_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) in NM_006941.4
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr22-37983381-C-G is described in Lovd as [Pathogenic].
PP3
MetaRNN computational evidence supports a deleterious effect, 0.985
PP5
Variant 22-37983382-T-C is Pathogenic according to our data. Variant chr22-37983382-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 692195.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr22-37983382-T-C is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SOX10 | NM_006941.4 | c.403A>G | p.Ser135Gly | missense_variant | 2/4 | ENST00000396884.8 | NP_008872.1 | |
POLR2F | NM_001301130.2 | c.294-2772T>C | intron_variant | NP_001288059.1 | ||||
POLR2F | NM_001363825.1 | c.*38+11072T>C | intron_variant | NP_001350754.1 | ||||
POLR2F | NM_001301131.2 | c.293+16212T>C | intron_variant | NP_001288060.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SOX10 | ENST00000396884.8 | c.403A>G | p.Ser135Gly | missense_variant | 2/4 | 1 | NM_006941.4 | ENSP00000380093.2 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD4 exome Cov.: 32
GnomAD4 exome
Cov.:
32
GnomAD4 genome Cov.: 32
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Waardenburg syndrome type 2E Pathogenic:1
Likely pathogenic, criteria provided, single submitter | research | Genetics Department, Polish Mother's Memorial Hospital Research Institute | Aug 27, 2019 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Pathogenic
D;D;D
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
.;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Uncertain
M;M;.
PrimateAI
Pathogenic
D
PROVEAN
Uncertain
D;D;D
REVEL
Pathogenic
Sift
Uncertain
D;D;D
Sift4G
Uncertain
D;D;.
Polyphen
D;D;.
Vest4
MutPred
Loss of stability (P = 0.0755);Loss of stability (P = 0.0755);Loss of stability (P = 0.0755);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at