22-37978112-C-T

Variant names:

• chr22-37978112-C-T
• rs1373797370
• NM_006941.4:c.452G>A

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 8P and 1B. PM1 PM2 PM5 PP3_Moderate BS2_Supporting

The NM_006941.4(SOX10):​c.452G>A​(p.Arg151His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000035 in 1,428,290 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R151C) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000035 (0 hom.)
• Consequence: SOX10 NM_006941.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.91

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 Likely_pathogenic. Variant got 7 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 chr22-37978113-G-A is described in Lovd as [Likely_pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.896
• 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	c.452G>A	p.Arg151His	missense_variant	Exon 3 of 4	ENST00000396884.8	NP_008872.1
POLR2F	NM_001301130.2	c.294-8042C>T		intron_variant	Intron 4 of 5		NP_001288059.1
POLR2F	NM_001363825.1	c.*38+5802C>T		intron_variant	Intron 5 of 5		NP_001350754.1
POLR2F	NM_001301131.2	c.293+10942C>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.452G>A	p.Arg151His	missense_variant	Exon 3 of 4	1	NM_006941.4	ENSP00000380093.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000350 AC: 5 AN: 1428290 Hom.: 0 Cov.: 32 AF XY: 0.00000425 AC XY: 3 AN XY: 706078

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000235

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: 0.00000366

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Apr 17, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SOX10 protein function. This variant has not been reported in the literature in individuals affected with SOX10-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 151 of the SOX10 protein (p.Arg151His). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.60
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.30
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.98	D;D;D
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	.;D;D
M_CAP	Pathogenic	0.47	D
MetaRNN	Pathogenic	0.90	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	1.3	L;L;.
PrimateAI	Pathogenic	0.92	D
PROVEAN	Uncertain	-4.4	D;D;D
REVEL	Pathogenic	0.90
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0010	D;D;.
Polyphen		1.0	D;D;.
Vest4		0.82
MutPred		0.59		Loss of MoRF binding (P = 0.0268);Loss of MoRF binding (P = 0.0268);Loss of MoRF binding (P = 0.0268);
MVP		0.94
MPC		2.1
ClinPred		0.99	D
GERP RS		4.5
Varity_R		0.76
gMVP		0.93

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

LitVar

Other links and lift over

dbSNP: rs1373797370; hg19: chr22-38374119; COSMIC: COSV100704065;