22-37978094-G-T

Variant names:

• chr22-37978094-G-T
• NM_006941.4:c.470C>A

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP3_Strong

The NM_006941.4(SOX10):​c.470C>A​(p.Ala157Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000694 in 1,441,676 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. A157V) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: SOX10 NM_006941.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 10.0

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

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM1: In a DNA_binding_region HMG box (size 68) in uniprot entity SOX10_HUMAN there are 27 pathogenic changes around while only 1 benign (96%) 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 chr22-37978094-G-A is described in Lovd as [Likely_pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.984

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SOX10	NM_006941.4	c.470C>A	p.Ala157Asp	missense_variant	Exon 3 of 4	ENST00000396884.8	NP_008872.1
POLR2F	NM_001301130.2	c.294-8060G>T		intron_variant	Intron 4 of 5		NP_001288059.1
POLR2F	NM_001363825.1	c.*38+5784G>T		intron_variant	Intron 5 of 5		NP_001350754.1
POLR2F	NM_001301131.2	c.293+10924G>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.470C>A	p.Ala157Asp	missense_variant	Exon 3 of 4	1	NM_006941.4	ENSP00000380093.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.94e-7 AC: 1 AN: 1441676 Hom.: 0 Cov.: 32 AF XY: 0.00000140 AC XY: 1 AN XY: 714352

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000230

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	D;D;D
Eigen	Uncertain	0.68
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	.;D;D
M_CAP	Pathogenic	0.42	D
MetaRNN	Pathogenic	0.98	D;D;D
MetaSVM	Uncertain	0.78	D
MutationAssessor	Pathogenic	4.4	H;H;.
PrimateAI	Pathogenic	0.94	D
PROVEAN	Pathogenic	-5.2	D;D;D
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0010	D;D;.
Polyphen		1.0	D;D;.
Vest4		0.97
MutPred		0.91		Loss of MoRF binding (P = 0.0738);Loss of MoRF binding (P = 0.0738);Loss of MoRF binding (P = 0.0738);
MVP		1.0
MPC		2.3
ClinPred		1.0	D
GERP RS		4.5
Varity_R		0.98
gMVP		1.0

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr22-38374101;