22-37983767-G-A

Position:

• chr22-37983767-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The ENST00000396884.8(SOX10):​c.18C>T​(p.Asp6=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0593 in 1,474,910 control chromosomes in the GnomAD database, including 2,830 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.070 (459 hom., cov: 32)
  • Exomes 𝑓: 0.058 (2371 hom.)
• Consequence: SOX10 ENST00000396884.8 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 3.02

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 22-37983767-G-A is Benign according to our data. Variant chr22-37983767-G-A is described in ClinVar as [Benign]. Clinvar id is 227078.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-37983767-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=3.02 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.105 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SOX10	NM_006941.4	c.18C>T	p.Asp6=	synonymous_variant	2/4	ENST00000396884.8	NP_008872.1
POLR2F	NM_001301130.2	c.294-2387G>A		intron_variant			NP_001288059.1
POLR2F	NM_001301131.2	c.293+16597G>A		intron_variant			NP_001288060.1
POLR2F	NM_001363825.1	c.*38+11457G>A		intron_variant			NP_001350754.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SOX10	ENST00000396884.8	c.18C>T	p.Asp6=	synonymous_variant	2/4	1	NM_006941.4	ENSP00000380093	P1

Frequencies

GnomAD3 genomes AF: 0.0701 AC: 10602 AN: 151258 Hom.: 460 Cov.: 32

Gnomad AFR AF: 0.108

Gnomad AMI AF: 0.0901

Gnomad AMR AF: 0.0465

Gnomad ASJ AF: 0.0289

Gnomad EAS AF: 0.0944

Gnomad SAS AF: 0.0638

Gnomad FIN AF: 0.0541

Gnomad MID AF: 0.0732

Gnomad NFE AF: 0.0552

Gnomad OTH AF: 0.0791

GnomAD3 exomes AF: 0.0554 AC: 5529 AN: 99714 Hom.: 188 AF XY: 0.0561 AC XY: 3147 AN XY: 56096

Gnomad AFR exome AF: 0.130

Gnomad AMR exome AF: 0.0305

Gnomad ASJ exome AF: 0.0285

Gnomad EAS exome AF: 0.109

Gnomad SAS exome AF: 0.0651

Gnomad FIN exome AF: 0.0498

Gnomad NFE exome AF: 0.0557

Gnomad OTH exome AF: 0.0574

GnomAD4 exome AF: 0.0581 AC: 76853 AN: 1323542 Hom.: 2371 Cov.: 32 AF XY: 0.0579 AC XY: 37801 AN XY: 653280

Gnomad4 AFR exome AF: 0.112

Gnomad4 AMR exome AF: 0.0343

Gnomad4 ASJ exome AF: 0.0291

Gnomad4 EAS exome AF: 0.0890

Gnomad4 SAS exome AF: 0.0662

Gnomad4 FIN exome AF: 0.0517

Gnomad4 NFE exome AF: 0.0567

Gnomad4 OTH exome AF: 0.0586

GnomAD4 genome AF: 0.0701 AC: 10604 AN: 151368 Hom.: 459 Cov.: 32 AF XY: 0.0699 AC XY: 5171 AN XY: 73990

Gnomad4 AFR AF: 0.107

Gnomad4 AMR AF: 0.0464

Gnomad4 ASJ AF: 0.0289

Gnomad4 EAS AF: 0.0947

Gnomad4 SAS AF: 0.0632

Gnomad4 FIN AF: 0.0541

Gnomad4 NFE AF: 0.0552

Gnomad4 OTH AF: 0.0811

Alfa AF: 0.0357 Hom.: 43

Asia WGS AF: 0.0650 AC: 219 AN: 3366

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 24, 2014	Asp6Asp in exon 2 of SOX10: This variant is not expected to have clinical signif icance because it does not alter an amino acid residue and is not located within the splice consensus sequence. It has been identified in 6.4% (102/1590) of Afr ican American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS; dbSNP rs149435516). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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	GeneDx	Sep 13, 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:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 31, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

PCWH syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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. -

Waardenburg syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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	-0.46
CADD	Benign	12
DANN	Uncertain	0.98

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: rs149435516; hg19: chr22-38379774; COSMIC: COSV61004948; COSMIC: COSV61004948;