22-37975389-G-C

Variant names:

• chr22-37975389-G-C
• rs139887
• NM_006941.4:c.698-1191C>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_006941.4(SOX10):​c.698-1191C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.593 in 151,996 control chromosomes in the GnomAD database, including 26,962 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.59 (26962 hom., cov: 31)
• Consequence: SOX10 NM_006941.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.375
• Publications: 14 publications found

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

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• 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.698-1191C>G		intron_variant	Intron 3 of 3	ENST00000396884.8	NP_008872.1
POLR2F	NM_001301130.2	c.293+8219G>C		intron_variant	Intron 4 of 5		NP_001288059.1
POLR2F	NM_001363825.1	c.*38+3079G>C		intron_variant	Intron 5 of 5		NP_001350754.1
POLR2F	NM_001301131.2	c.293+8219G>C		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	c.698-1191C>G		intron_variant	Intron 3 of 3	1	NM_006941.4	ENSP00000380093.2

Frequencies

GnomAD3 genomes AF: 0.593 AC: 90056 AN: 151878 Hom.: 26962 Cov.: 31

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: 0.608

Gnomad NFE AF: 0.626

Gnomad OTH AF: 0.593

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.593 AC: 90090 AN: 151996 Hom.: 26962 Cov.: 31 AF XY: 0.592 AC XY: 43983 AN XY: 74288

African (AFR) AF: 0.507 AC: 20999 AN: 41444

American (AMR) AF: 0.603 AC: 9213 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.589 AC: 2043 AN: 3470

East Asian (EAS) AF: 0.746 AC: 3856 AN: 5166

South Asian (SAS) AF: 0.623 AC: 3004 AN: 4820

European-Finnish (FIN) AF: 0.615 AC: 6489 AN: 10556

Middle Eastern (MID) AF: 0.630 AC: 184 AN: 292

European-Non Finnish (NFE) AF: 0.626 AC: 42548 AN: 67958

Other (OTH) AF: 0.592 AC: 1248 AN: 2108

Alfa AF: 0.484 Hom.: 1358

Bravo AF: 0.588

Asia WGS AF: 0.656 AC: 2285 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	3.1
DANN	Benign	0.70
PhyloP100		-0.38
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs139887; hg19: chr22-38371396;