22-37973020-C-T

Position:

chr22-37973020-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_006941.4(SOX10):c.*475G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.593 in 156,852 control chromosomes in the GnomAD database, including 27,906 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.59 ( 26935 hom., cov: 32)

Exomes 𝑓: 0.62 ( 971 hom. )

Consequence

SOX10
NM_006941.4 3_prime_UTR

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -1.50

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.92).

BP6

Variant 22-37973020-C-T is Benign according to our data. Variant chr22-37973020-C-T is described in ClinVar as [Benign]. Clinvar id is 341614.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.727 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	#exon/exons	MANE
SOX10	NM_006941.4 linkuse as main transcript	c.*475G>A	3_prime_UTR_variant	4/4	ENST00000396884.8
POLR2F	NM_001301130.2 linkuse as main transcript	c.293+5850C>T	intron_variant
POLR2F	NM_001301131.2 linkuse as main transcript	c.293+5850C>T	intron_variant
POLR2F	NM_001363825.1 linkuse as main transcript	c.*38+710C>T	intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SOX10	ENST00000396884.8 linkuse as main transcript	c.*475G>A		3_prime_UTR_variant	4/4	1	NM_006941.4	P1	P56693-1

Frequencies

GnomAD3 genomes

AF:

0.593

AC:

90021

AN:

151876

Hom.:

26935

Cov.:

show subpopulations

Gnomad AFR

AF:

0.507

Gnomad AMI

AF:

0.556

Gnomad AMR

AF:

0.603

Gnomad ASJ

AF:

0.589

Gnomad EAS

AF:

0.747

Gnomad SAS

AF:

0.622

Gnomad FIN

AF:

0.615

Gnomad MID

AF:

0.611

Gnomad NFE

AF:

0.626

Gnomad OTH

AF:

0.593

GnomAD4 exome

AF:

0.624

AC:

3030

AN:

4858

Hom.:

971

Cov.:

AF XY:

0.626

AC XY:

1589

AN XY:

2538

show subpopulations

Gnomad4 AFR exome

AF:

0.481

Gnomad4 AMR exome

AF:

0.614

Gnomad4 ASJ exome

AF:

0.563

Gnomad4 EAS exome

AF:

0.771

Gnomad4 SAS exome

AF:

0.645

Gnomad4 FIN exome

AF:

0.678

Gnomad4 NFE exome

AF:

0.628

Gnomad4 OTH exome

AF:

0.573

GnomAD4 genome

AF:

0.592

AC:

90055

AN:

151994

Hom.:

26935

Cov.:

AF XY:

0.592

AC XY:

43990

AN XY:

74302

show subpopulations

Gnomad4 AFR

AF:

0.506

Gnomad4 AMR

AF:

0.603

Gnomad4 ASJ

AF:

0.589

Gnomad4 EAS

AF:

0.747

Gnomad4 SAS

AF:

0.623

Gnomad4 FIN

AF:

0.615

Gnomad4 NFE

AF:

0.626

Gnomad4 OTH

AF:

0.592

Alfa

AF:

0.613

Hom.:

24482

Bravo

AF:

0.588

Asia WGS

AF:

0.654

AC:

2275

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

PCWH 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. -

Waardenburg syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.92

CADD

Benign

0.16

DANN

Benign

0.60

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