rs1555939403

Positions:

• chr22-37983359-C-A
• chr22-37983359-C-G
• chr22-37983359-C-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP3_Strong PP5

The NM_006941.4(SOX10):​c.426G>T​(p.Trp142Cys) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. W142R) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SOX10 NM_006941.4 missense, splice_region
• Scores: Splicing: ADA: 0.8400
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.68

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]

SOX10 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 11 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 chr22-37983361-A-G is described in Lovd as [Likely_pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.988
• PP5: Variant 22-37983359-C-A is Pathogenic according to our data. Variant chr22-37983359-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 801016.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SOX10	NM_006941.4	c.426G>T	p.Trp142Cys	missense_variant, splice_region_variant	2/4	ENST00000396884.8	NP_008872.1
POLR2F	NM_001301130.2	c.294-2795C>A		intron_variant			NP_001288059.1
POLR2F	NM_001363825.1	c.*38+11049C>A		intron_variant			NP_001350754.1
POLR2F	NM_001301131.2	c.293+16189C>A		intron_variant			NP_001288060.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SOX10	ENST00000396884.8	c.426G>T	p.Trp142Cys	missense_variant, splice_region_variant	2/4	1	NM_006941.4	ENSP00000380093.2

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

Submissions by phenotype

Waardenburg syndrome type 2E Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Hearing and Balance Clinic, First Affliiated Hospital of Kunming Medical University

Dec 26, 2019

The proband was a 4-year-old boy who suffered from congenital bilateral profound hearing loss. He was delivered full-term with a bilateral blue iris and normal inner canthi. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	36
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.99	D;D;D
Eigen	Pathogenic	0.96
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	.;D;D
M_CAP	Pathogenic	0.96	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	0.95	D
MutationAssessor	Pathogenic	4.5	H;H;.
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-11	D;D;D
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0010	D;D;.
Polyphen		1.0	D;D;.
Vest4		0.93
MutPred		0.87		Loss of MoRF binding (P = 0.0109);Loss of MoRF binding (P = 0.0109);Loss of MoRF binding (P = 0.0109);
MVP		0.98
MPC		2.4
ClinPred		1.0	D
GERP RS		4.4
Varity_R		0.96
gMVP		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.84
dbscSNV1_RF	Benign	0.65
SpliceAI score (max)		0.080		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

Other links and lift over

dbSNP: rs1555939403; hg19: chr22-38379366;