22-37983654-G-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM2BP4_ModerateBS2_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

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.67

Publications

4 publications found

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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 link	c.131C>A	p.Ala44Asp	missense_variant	Exon 2 of 4	ENST00000396884.8	NP_008872.1	P56693-1A0A024R1N6
POLR2F	NM_001301130.2 link	c.294-2500G>T		intron_variant	Intron 4 of 5		NP_001288059.1	B0QYL9
POLR2F	NM_001363825.1 link	c.*38+11344G>T		intron_variant	Intron 5 of 5		NP_001350754.1
POLR2F	NM_001301131.2 link	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 link	c.131C>A	p.Ala44Asp	missense_variant	Exon 2 of 4	1	NM_006941.4	ENSP00000380093.2		P56693-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000462

AC:

AN:

216662

AF XY:

0.00000839

show subpopulations

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:

AN:

1442058

Hom.:

Cov.:

AF XY:

0.00000558

AC XY:

AN XY:

717080

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33262

American (AMR)

AF:

0.00

AC:

AN:

43690

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25874

East Asian (EAS)

AF:

0.00

AC:

AN:

39144

South Asian (SAS)

AF:

0.00

AC:

AN:

84902

European-Finnish (FIN)

AF:

0.00

AC:

AN:

42272

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5580

European-Non Finnish (NFE)

AF:

0.00000451

AC:

AN:

1107580

Other (OTH)

AF:

0.00

AC:

AN:

59754

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

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

BayesDel_noAF

Benign

-0.32

CADD

Benign

(source)

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

LIST_S2

Benign

0.55

.;T;T

M_CAP

Pathogenic

0.43

MetaRNN

Benign

0.25

T;T;T

MetaSVM

Benign

-0.63

MutationAssessor

Benign

1.5

L;L;.

PhyloP100

1.7

PrimateAI

Pathogenic

0.88

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

GERP RS

4.3

PromoterAI

-0.044

Neutral

(source)

Varity_R

0.17

gMVP

0.34

Mutation Taster

=61/39

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over