chr22-37973969-A-G

Position:

chr22-37973969-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_006941.4(SOX10):c.927T>C(p.His309His) 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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:14

Conservation

PhyloP100: -1.28

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]

SOX10 links:

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]

POLR2F links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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	Protein	UniProt
SOX10	NM_006941.4 linkuse as main transcript	c.927T>C	p.His309His	synonymous_variant	4/4	ENST00000396884.8	NP_008872.1	P56693-1A0A024R1N6
POLR2F	NM_001301130.2 linkuse as main transcript	c.293+6799A>G		intron_variant			NP_001288059.1	B0QYL9
POLR2F	NM_001363825.1 linkuse as main transcript	c.*38+1659A>G		intron_variant			NP_001350754.1
POLR2F	NM_001301131.2 linkuse as main transcript	c.293+6799A>G		intron_variant			NP_001288060.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SOX10	ENST00000396884.8 linkuse as main transcript	c.927T>C	p.His309His	synonymous_variant	4/4	1	NM_006941.4	ENSP00000380093.2		P56693-1

Frequencies

GnomAD3 genomes

AF:

0.685

AC:

104187

AN:

152088

Hom.:

36348

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.638

AC XY:

463571

AN XY:

726180

show subpopulations

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.:

AF XY:

0.682

AC XY:

50722

AN XY:

74406

show subpopulations

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:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:7

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
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, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 23, 2017	- -
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. -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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

- -

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over