22-37973020-C-T

Variant names:

• chr22-37973020-C-T
• rs139883
• NM_006941.4:c.*475G>A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.50

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 -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	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SOX10	NM_006941.4	c.*475G>A		3_prime_UTR_variant	Exon 4 of 4	ENST00000396884.8	NP_008872.1
POLR2F	NM_001301130.2	c.293+5850C>T		intron_variant	Intron 4 of 5		NP_001288059.1
POLR2F	NM_001363825.1	c.*38+710C>T		intron_variant	Intron 5 of 5		NP_001350754.1
POLR2F	NM_001301131.2	c.293+5850C>T		intron_variant	Intron 4 of 4		NP_001288060.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SOX10	ENST00000396884	c.*475G>A		3_prime_UTR_variant	Exon 4 of 4	1	NM_006941.4	ENSP00000380093.2

Frequencies

GnomAD3 genomes AF: 0.593 AC: 90021 AN: 151876 Hom.: 26935 Cov.: 32

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.: 0 AF XY: 0.626 AC XY: 1589 AN XY: 2538

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.: 32 AF XY: 0.592 AC XY: 43990 AN XY: 74302

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

Submissions by phenotype

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

PCWH syndrome Benign:1

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. -

Waardenburg syndrome Benign:1

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. -

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

Other links and lift over

dbSNP: rs139883; hg19: chr22-38369027;