NM_006941.4:c.131C>A

Variant names:

• chr22-37983654-G-T
• rs747377284
• NM_006941.4:c.131C>A

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BS2_Supporting

The NM_006941.4(SOX10):​c.131C>A​(p.Ala44Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000347 in 1,442,058 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A44G) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000035 (0 hom.)
• Consequence: SOX10 NM_006941.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.67
• Publications: 4 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: Likely_benign. The variant received -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.25141883).
• BS2: High AC in GnomAdExome4 at 5 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SOX10	NM_006941.4	c.131C>A	p.Ala44Asp	missense_variant	Exon 2 of 4	ENST00000396884.8	NP_008872.1
POLR2F	NM_001301130.2	c.294-2500G>T		intron_variant	Intron 4 of 5		NP_001288059.1
POLR2F	NM_001363825.1	c.*38+11344G>T		intron_variant	Intron 5 of 5		NP_001350754.1
POLR2F	NM_001301131.2	c.293+16484G>T		intron_variant	Intron 4 of 4		NP_001288060.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SOX10	ENST00000396884.8	c.131C>A	p.Ala44Asp	missense_variant	Exon 2 of 4	1	NM_006941.4	ENSP00000380093.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000462 AC: 1 AN: 216662 AF XY: 0.00000839

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000103

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000347 AC: 5 AN: 1442058 Hom.: 0 Cov.: 32 AF XY: 0.00000558 AC XY: 4 AN XY: 717080

African (AFR) AF: 0.00 AC: 0 AN: 33262

American (AMR) AF: 0.00 AC: 0 AN: 43690

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25874

East Asian (EAS) AF: 0.00 AC: 0 AN: 39144

South Asian (SAS) AF: 0.00 AC: 0 AN: 84902

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 42272

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5580

European-Non Finnish (NFE) AF: 0.00000451 AC: 5 AN: 1107580

Other (OTH) AF: 0.00 AC: 0 AN: 59754

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.059	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.42	T;T;T
Eigen	Benign	-0.13
Eigen_PC	Benign	0.014
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.55	.;T;T
M_CAP	Pathogenic	0.43	D
MetaRNN	Benign	0.25	T;T;T
MetaSVM	Benign	-0.63	T
MutationAssessor	Benign	1.5	L;L;.
PhyloP100		1.7
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	0.030	N;N;N
REVEL	Benign	0.21
Sift	Benign	0.23	T;T;T
Sift4G	Benign	0.51	T;T;.
Polyphen		0.16	B;B;.
Vest4		0.20
MutPred		0.27		Gain of relative solvent accessibility (P = 0.0082);Gain of relative solvent accessibility (P = 0.0082);Gain of relative solvent accessibility (P = 0.0082);
MVP		0.44
MPC		1.2
ClinPred		0.13	T
GERP RS		4.3
PromoterAI		-0.044	Neutral
Varity_R		0.17
gMVP		0.34
Mutation Taster		=61/39	polymorphism

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: rs747377284; hg19: chr22-38379661;