chr22-37983767-G-T

Variant names:

• chr22-37983767-G-T
• rs149435516
• NM_006941.4:c.18C>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_006941.4(SOX10):​c.18C>A​(p.Asp6Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. D6D) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SOX10 NM_006941.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.02
• Publications: 11 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.34285256).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SOX10	NM_006941.4	MANE Select	c.18C>A	p.Asp6Glu	missense	Exon 2 of 4	NP_008872.1
	POLR2F	NM_001301130.2		c.294-2387G>T		intron	N/A	NP_001288059.1
	POLR2F	NM_001363825.1		c.*38+11457G>T		intron	N/A	NP_001350754.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SOX10	ENST00000396884.8	TSL:1 MANE Select	c.18C>A	p.Asp6Glu	missense	Exon 2 of 4	ENSP00000380093.2
	SOX10	ENST00000360880.6	TSL:1	c.18C>A	p.Asp6Glu	missense	Exon 3 of 5	ENSP00000354130.2
	SOX10	ENST00000698177.1		c.234C>A	p.Asp78Glu	missense	Exon 3 of 5	ENSP00000513596.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1323920 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 653466

African (AFR) AF: 0.00 AC: 0 AN: 26666

American (AMR) AF: 0.00 AC: 0 AN: 28734

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22774

East Asian (EAS) AF: 0.00 AC: 0 AN: 29932

South Asian (SAS) AF: 0.00 AC: 0 AN: 74444

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32748

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4230

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1050162

Other (OTH) AF: 0.00 AC: 0 AN: 54230

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 43

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.0084	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.36	T
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.078
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.89	D
MetaRNN	Benign	0.34	T
MetaSVM	Uncertain	0.19	D
MutationAssessor	Benign	0.57	N
PhyloP100		3.0
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-0.66	N
REVEL	Uncertain	0.33
Sift	Benign	0.16	T
Sift4G	Benign	0.38	T
Polyphen		0.0	B
Vest4		0.067
MutPred		0.24		Gain of sheet (P = 0.0827)
MVP		0.87
MPC		0.82
ClinPred		0.40	T
GERP RS		2.7
PromoterAI		0.10	Neutral
Varity_R		0.11
gMVP		0.16
Mutation Taster		=92/8	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: rs149435516; hg19: chr22-38379774;