22-37973969-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -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

Publications

39 publications found

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 was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 227081.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 rank	MANE	Protein
SOX10	NM_006941.4 link	c.927T>C	p.His309His	synonymous_variant	Exon 4 of 4	ENST00000396884.8	NP_008872.1
POLR2F	NM_001301130.2 link	c.293+6799A>G		intron_variant	Intron 4 of 5		NP_001288059.1
POLR2F	NM_001363825.1 link	c.*38+1659A>G		intron_variant	Intron 5 of 5		NP_001350754.1
POLR2F	NM_001301131.2 link	c.293+6799A>G		intron_variant	Intron 4 of 4		NP_001288060.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SOX10	ENST00000396884.8 link	c.927T>C	p.His309His	synonymous_variant	Exon 4 of 4	1	NM_006941.4	ENSP00000380093.2

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

GnomAD2 exomes

AF:

0.650

AC:

161930

AN:

249110

AF XY:

0.645

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 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

African (AFR)

AF:

0.829

AC:

27760

AN:

33478

American (AMR)

AF:

0.626

AC:

28003

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.601

AC:

15702

AN:

26134

East Asian (EAS)

AF:

0.728

AC:

28890

AN:

39700

South Asian (SAS)

AF:

0.632

AC:

54546

AN:

86254

European-Finnish (FIN)

AF:

0.627

AC:

32116

AN:

51242

Middle Eastern (MID)

AF:

0.652

AC:

3757

AN:

5762

European-Non Finnish (NFE)

AF:

0.632

AC:

703023

AN:

1111864

Other (OTH)

AF:

0.653

AC:

39413

AN:

60360

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

23282

46565

69847

93130

116412

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

18776

37552

56328

75104

93880

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.685

AC:

104298

AN:

152206

Hom.:

36393

Cov.:

AF XY:

0.682

AC XY:

50722

AN XY:

74406

show subpopulations

African (AFR)

AF:

0.823

AC:

34181

AN:

41532

American (AMR)

AF:

0.640

AC:

9787

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.597

AC:

2073

AN:

3470

East Asian (EAS)

AF:

0.757

AC:

3916

AN:

5174

South Asian (SAS)

AF:

0.624

AC:

3006

AN:

4820

European-Finnish (FIN)

AF:

0.615

AC:

6520

AN:

10596

Middle Eastern (MID)

AF:

0.643

AC:

189

AN:

294

European-Non Finnish (NFE)

AF:

0.628

AC:

42739

AN:

68004

Other (OTH)

AF:

0.655

AC:

1383

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1684

3368

5052

6736

8420

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

814

1628

2442

3256

4070

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.641

Hom.:

41759

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

Jan 23, 2017

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Nov 24, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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).

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

May 09, 2017

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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.

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PCWH syndrome

Benign:2

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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.

Jul 15, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Waardenburg syndrome type 2E

Benign:1

Jul 15, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Waardenburg syndrome type 4C

Benign:1

Jul 15, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Waardenburg syndrome

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.89

CADD

Benign

0.080

(source)

DANN

Benign

0.47

PhyloP100

-1.3

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over