rs139884

chr22-37973969-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_006941.4(SOX10):c.927T>C(p.His309=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.644 in 1,611,716 control chromosomes in the GnomAD database, including 336,474 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.69 (36393 hom., cov: 34)
  • Exomes 𝑓: 0.64 (300081 hom.)
• Consequence: SOX10 NM_006941.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: -1.28

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 Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 22-37973969-A-G is Benign according to our data. Variant chr22-37973969-A-G is described in ClinVar as [Benign]. Clinvar id is 227081.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-37973969-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.28 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.816 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SOX10	NM_006941.4	c.927T>C	p.His309=	synonymous_variant	4/4	ENST00000396884.8
POLR2F	NM_001301130.2	c.293+6799A>G		intron_variant
POLR2F	NM_001301131.2	c.293+6799A>G		intron_variant
POLR2F	NM_001363825.1	c.*38+1659A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SOX10	ENST00000396884.8	c.927T>C	p.His309=	synonymous_variant	4/4	1	NM_006941.4	P1

Frequencies

GnomAD3 genomes AF: 0.685 AC: 104187 AN: 152088 Hom.: 36348 Cov.: 34

Gnomad AFR AF: 0.823

Gnomad AMI AF: 0.555

Gnomad AMR AF: 0.640

Gnomad ASJ AF: 0.597

Gnomad EAS AF: 0.757

Gnomad SAS AF: 0.623

Gnomad FIN AF: 0.615

Gnomad MID AF: 0.620

Gnomad NFE AF: 0.628

Gnomad OTH AF: 0.657

GnomAD3 exomes AF: 0.650 AC: 161930 AN: 249110 Hom.: 53122 AF XY: 0.645 AC XY: 86911 AN XY: 134838

Gnomad AFR exome AF: 0.826

Gnomad AMR exome AF: 0.623

Gnomad ASJ exome AF: 0.595

Gnomad EAS exome AF: 0.760

Gnomad SAS exome AF: 0.634

Gnomad FIN exome AF: 0.628

Gnomad NFE exome AF: 0.629

Gnomad OTH exome AF: 0.637

GnomAD4 exome AF: 0.639 AC: 933210 AN: 1459510 Hom.: 300081 Cov.: 63 AF XY: 0.638 AC XY: 463571 AN XY: 726180

Gnomad4 AFR exome AF: 0.829

Gnomad4 AMR exome AF: 0.626

Gnomad4 ASJ exome AF: 0.601

Gnomad4 EAS exome AF: 0.728

Gnomad4 SAS exome AF: 0.632

Gnomad4 FIN exome AF: 0.627

Gnomad4 NFE exome AF: 0.632

Gnomad4 OTH exome AF: 0.653

GnomAD4 genome AF: 0.685 AC: 104298 AN: 152206 Hom.: 36393 Cov.: 34 AF XY: 0.682 AC XY: 50722 AN XY: 74406

Gnomad4 AFR AF: 0.823

Gnomad4 AMR AF: 0.640

Gnomad4 ASJ AF: 0.597

Gnomad4 EAS AF: 0.757

Gnomad4 SAS AF: 0.624

Gnomad4 FIN AF: 0.615

Gnomad4 NFE AF: 0.628

Gnomad4 OTH AF: 0.655

Alfa AF: 0.633 Hom.: 32061

Bravo AF: 0.694

Asia WGS AF: 0.682 AC: 2376 AN: 3478

EpiCase AF: 0.624

EpiControl AF: 0.621

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:7

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 09, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 23, 2017	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 24, 2014	His309His in exon 4 of SOX10: This variant is not expected to have clinical sign ificance because it does not alter an amino acid residue and is not located with in the splice consensus sequence. It has been identified in 36.6% (3149/8600) of European American chromosomes from a broad population by the NHLBI Exome Sequen cing Project (http://evs.gs.washington.edu/EVS; dbSNP rs139884). -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

PCWH syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -

Waardenburg syndrome type 2E Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 15, 2021

- -

Waardenburg syndrome type 4C Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 15, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Waardenburg syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
Cadd	Benign	0.080
Dann	Benign	0.47

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: rs139884; hg19: chr22-38369976; COSMIC: COSV62807092; COSMIC: COSV62807092;