rs1555939415

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

Scores

9
9
1

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 4.99
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]

Genome browser will be placed here

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
SOX10NM_006941.4 linkuse as main transcriptc.403A>G p.Ser135Gly missense_variant 2/4 ENST00000396884.8 NP_008872.1 P56693-1A0A024R1N6
POLR2FNM_001301130.2 linkuse as main transcriptc.294-2772T>C intron_variant NP_001288059.1 B0QYL9
POLR2FNM_001363825.1 linkuse as main transcriptc.*38+11072T>C intron_variant NP_001350754.1
POLR2FNM_001301131.2 linkuse as main transcriptc.293+16212T>C intron_variant NP_001288060.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
SOX10ENST00000396884.8 linkuse as main transcriptc.403A>G p.Ser135Gly missense_variant 2/41 NM_006941.4 ENSP00000380093.2 P56693-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
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 submitterresearchGenetics Department, Polish Mother's Memorial Hospital Research InstituteAug 27, 2019- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.50
D
BayesDel_noAF
Pathogenic
0.47
CADD
Pathogenic
32
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.98
D;D;D
Eigen
Uncertain
0.61
Eigen_PC
Uncertain
0.56
FATHMM_MKL
Uncertain
0.94
D
LIST_S2
Uncertain
0.96
.;D;D
M_CAP
Pathogenic
0.91
D
MetaRNN
Pathogenic
0.99
D;D;D
MetaSVM
Pathogenic
0.96
D
MutationAssessor
Uncertain
2.8
M;M;.
PrimateAI
Pathogenic
0.87
D
PROVEAN
Uncertain
-3.5
D;D;D
REVEL
Pathogenic
0.94
Sift
Uncertain
0.0020
D;D;D
Sift4G
Uncertain
0.0040
D;D;.
Polyphen
0.96
D;D;.
Vest4
0.75
MutPred
0.92
Loss of stability (P = 0.0755);Loss of stability (P = 0.0755);Loss of stability (P = 0.0755);
MVP
1.0
MPC
1.8
ClinPred
0.98
D
GERP RS
4.4
Varity_R
0.91
gMVP
0.99

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

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: rs1555939415; hg19: chr22-38379389; API