rs1555939408

chr22-37983361-A-G

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_006941.4(SOX10):c.424T>C(p.Trp142Arg) variant causes a missense 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. 12/20 in silico tools predict a damaging 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. W142C) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SOX10 NM_006941.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 9.06

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

Verdict is Pathogenic. Variant got 18 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain 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 chr22-37983359-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 547781.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.987
• PP5: Variant 22-37983361-A-G is Pathogenic according to our data. Variant chr22-37983361-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 505653.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-37983361-A-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SOX10	NM_006941.4	c.424T>C	p.Trp142Arg	missense_variant	2/4	ENST00000396884.8
POLR2F	NM_001301130.2	c.294-2793A>G		intron_variant
POLR2F	NM_001301131.2	c.293+16191A>G		intron_variant
POLR2F	NM_001363825.1	c.*38+11051A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SOX10	ENST00000396884.8	c.424T>C	p.Trp142Arg	missense_variant	2/4	1	NM_006941.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Waardenburg syndrome type 2E Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genetic Testing Center for Deafness, Department of Otolaryngology Head & Neck Surgery, Institute of Otolaryngology, Chinese PLA General Hospital

Jan 01, 2019

- -

Rare genetic deafness Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jun 20, 2017

The p.Trp142Arg variant in SOX10 has been reported in one individual with Kallma nn syndrome who had prelingual hearing loss and temporal bone abnormalities, inc luding hypoplasia of the semicircular canals and an enlarged vestibular aqueduct (Pingault 2013). It has also been reported by our laboratory to have likely occ urred de novo in 1 individual with congenital hearing loss and enlarged vestibul ar aqueducts, though parental identity has not been confirmed. This variant has not been identified in large population studies. In vitro studies showed that th e p.Trp142Arg variant altered the ability of SOX10 to localize to the nucleus an d to transactivate MITF and MPZ genes (Pingault 2013). Computational prediction tools and conservation analyses suggest that this variant may impact the protein . In summary, although additional studies are required to fully establish its c linical significance, this variant is likely pathogenic for autosomal dominant h earing loss with temporal bone abnormalities based on its presence in multiple a ffected individuals, likely de novo occurrence, extremely low frequency in the g eneral population, and supportive functional evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.59	D
BayesDel_noAF	Pathogenic	0.60
Cadd	Pathogenic	34
Dann	Uncertain	0.99
DEOGEN2	Pathogenic	0.99	D;D;D
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Pathogenic	0.98	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	0.99	D
MutationAssessor	Pathogenic	4.1	H;H;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-12	D;D;D
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0010	D;D;.
Polyphen		1.0	D;D;.
Vest4		0.98
MutPred		0.86		Gain of disorder (P = 4e-04);Gain of disorder (P = 4e-04);Gain of disorder (P = 4e-04);
MVP		0.99
MPC		2.5
ClinPred		1.0	D
GERP RS		4.4
Varity_R		0.98
gMVP		1.0

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

Other links and lift over

dbSNP: rs1555939408; hg19: chr22-38379368;