chr22-37983384-A-G

Position:

• chr22-37983384-A-G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PP3_Strong PP5_Moderate

The NM_006941.4(SOX10):​c.401T>C​(p.Leu134Pro) 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. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SOX10 NM_006941.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.31

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 10 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
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.973
• PP5: Variant 22-37983384-A-G is Pathogenic according to our data. Variant chr22-37983384-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 228291.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SOX10	NM_006941.4	c.401T>C	p.Leu134Pro	missense_variant	2/4	ENST00000396884.8	NP_008872.1
POLR2F	NM_001301130.2	c.294-2770A>G		intron_variant			NP_001288059.1
POLR2F	NM_001301131.2	c.293+16214A>G		intron_variant			NP_001288060.1
POLR2F	NM_001363825.1	c.*38+11074A>G		intron_variant			NP_001350754.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SOX10	ENST00000396884.8	c.401T>C	p.Leu134Pro	missense_variant	2/4	1	NM_006941.4	ENSP00000380093	P1

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

Submissions by phenotype

Rare genetic deafness Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Feb 09, 2016

The p.Leu134Pro variant in SOX10 has been previously was reported in one indivi dual with hearing loss and inner ear malformations by our laboratory, and parent al testing revealed that the variant occurred de novo in this individual. The va riant was absent from large population studies. Computational prediction tools a nd conservation analyses suggest that the p.Leu134Pro variant may impact the pro tein and the variant occurs in the highly conserved HMG domain which is critical to the function of the protein (Wissmuller 2006). In addition, several de novo variants in the SOX10 gene have been reported in individuals with temporal bone abnormalities and other features of Waardenburg syndrome (Elmaleh-Berges 2013, Pingault 2015). In summary, although additional studies are required to fully es tablish its clinical significance, this variant is likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	D;D;D
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.94	.;D;D
M_CAP	Pathogenic	0.92	D
MetaRNN	Pathogenic	0.97	D;D;D
MetaSVM	Uncertain	0.011	D
MutationAssessor	Pathogenic	3.0	M;M;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.93	D
PROVEAN	Pathogenic	-5.8	D;D;D
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0010	D;D;.
Polyphen		1.0	D;D;.
Vest4		0.84
MutPred		0.85		Loss of stability (P = 0.0238);Loss of stability (P = 0.0238);Loss of stability (P = 0.0238);
MVP		1.0
MPC		2.4
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: rs876657660; hg19: chr22-38379391;