chr22-37983382-T-G

Variant names:

• chr22-37983382-T-G
• rs1555939415
• NM_006941.4:c.403A>C

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Moderate

The NM_006941.4(SOX10):​c.403A>C​(p.Ser135Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S135T) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SOX10 NM_006941.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 4.99
• Publications: 0 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: Pathogenic. The variant received 12 ACMG points.

• PM1: In a hotspot region, there are 17 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_006941.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr22-37983381-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 7397.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.987
• PP5: Variant 22-37983382-T-G is Pathogenic according to our data. Variant chr22-37983382-T-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 488043.Status of the report is criteria_provided_single_submitter, 1 stars.

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.403A>C	p.Ser135Arg	missense	Exon 2 of 4	NP_008872.1
	POLR2F	NM_001301130.2		c.294-2772T>G		intron	N/A	NP_001288059.1
	POLR2F	NM_001363825.1		c.*38+11072T>G		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.403A>C	p.Ser135Arg	missense	Exon 2 of 4	ENSP00000380093.2
	SOX10	ENST00000360880.6	TSL:1	c.403A>C	p.Ser135Arg	missense	Exon 3 of 5	ENSP00000354130.2
	SOX10	ENST00000698177.1		c.619A>C	p.Ser207Arg	missense	Exon 3 of 5	ENSP00000513596.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Waardenburg syndrome type 2A Pathogenic:1

Mar 01, 2017

Laboratory of Human Genetics, Universidade de São Paulo

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.52
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	D
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.98	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.3	H
PhyloP100		5.0
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-4.5	D
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.92
MutPred		0.90		Gain of MoRF binding (P = 0.0167)
MVP		0.99
MPC		2.0
ClinPred		1.0	D
GERP RS		4.4
PromoterAI		-0.0036	Neutral
Varity_R		0.98
gMVP		1.0
Mutation Taster		=1/99	disease causing (ClinVar)

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: rs1555939415; hg19: chr22-38379389;