Genetic Variant NM_006941.4:c.753G>A (chr22-37974143-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_ModerateBP6BP7BS1BS2

The NM_006941.4(SOX10):c.753G>A(p.Ser251Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000398 in 1,611,248 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. S251S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00034 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00040 ( 0 hom. )

Consequence

SOX10
NM_006941.4 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:6

Conservation

PhyloP100: -0.272

Publications

0 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:

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ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (REVEL=0.067).

BP6

Variant 22-37974143-C-T is Benign according to our data. Variant chr22-37974143-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 341617.

BP7

Synonymous conserved (PhyloP=-0.272 with no splicing effect.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000335 (51/152024) while in subpopulation EAS AF = 0.00193 (10/5174). AF 95% confidence interval is 0.00105. There are 0 homozygotes in GnomAd4. There are 26 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 51 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006941.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SOX10	NM_006941.4	MANE Select	c.753G>A	p.Ser251Ser	synonymous	Exon 4 of 4	NP_008872.1	P56693-1
POLR2F	NM_001301130.2		c.293+6973C>T		intron	N/A	NP_001288059.1	B0QYL9
POLR2F	NM_001363825.1		c.*38+1833C>T		intron	N/A	NP_001350754.1	F8WC47

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SOX10	ENST00000396884.8	TSL:1 MANE Select	c.753G>A	p.Ser251Ser	synonymous	Exon 4 of 4	ENSP00000380093.2	P56693-1
SOX10	ENST00000360880.6	TSL:1	c.753G>A	p.Ser251Ser	synonymous	Exon 5 of 5	ENSP00000354130.2	P56693-1
SOX10	ENST00000698177.1		c.969G>A	p.Ser323Ser	synonymous	Exon 5 of 5	ENSP00000513596.1	A0A8V8TM01

Frequencies

GnomAD3 genomes

AF:

0.000335

AC:

AN:

152024

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.00193

Gnomad SAS

AF:

0.000828

Gnomad FIN

AF:

0.0000944

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000368

Gnomad OTH

AF:

0.000960

GnomAD2 exomes

AF:

0.000557

AC:

137

AN:

246080

AF XY:

0.000546

show subpopulations

Gnomad AFR exome

AF:

0.000124

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00149

Gnomad EAS exome

AF:

0.00294

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000423

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000404

AC:

590

AN:

1459224

Hom.:

Cov.:

AF XY:

0.000419

AC XY:

304

AN XY:

726084

show subpopulations

African (AFR)

AF:

0.0000896

AC:

AN:

33478

American (AMR)

AF:

0.0000671

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00187

AC:

AN:

26136

East Asian (EAS)

AF:

0.00116

AC:

AN:

39698

South Asian (SAS)

AF:

0.000661

AC:

AN:

86250

European-Finnish (FIN)

AF:

0.0000197

AC:

AN:

50824

Middle Eastern (MID)

AF:

0.000174

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.000368

AC:

409

AN:

1111980

Other (OTH)

AF:

0.000348

AC:

AN:

60376

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

118

158

197

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<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

AF:

0.000335

AC:

AN:

152024

Hom.:

Cov.:

AF XY:

0.000350

AC XY:

AN XY:

74274

show subpopulations

African (AFR)

AF:

0.0000483

AC:

AN:

41374

American (AMR)

AF:

0.0000655

AC:

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.00173

AC:

AN:

3472

East Asian (EAS)

AF:

0.00193

AC:

AN:

5174

South Asian (SAS)

AF:

0.000828

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.0000944

AC:

AN:

10598

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000368

AC:

AN:

67994

Other (OTH)

AF:

0.000960

AC:

AN:

2084

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.000189

Hom.:

Bravo

AF:

0.000374

EpiCase

AF:

0.000545

EpiControl

AF:

0.000415

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

not specified (1)

PCWH syndrome (1)

Waardenburg syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.39

CADD

Benign

9.1

(source)

DANN

Benign

0.89

PhyloP100

-0.27

Mutation Taster

=99/1

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over