22-37973806-G-T

Variant names:

• chr22-37973806-G-T
• rs1555937400
• NM_006941.4:c.1090C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_006941.4(SOX10):​c.1090C>A​(p.Gln364Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000692 in 1,444,128 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign 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. Q364P) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: SOX10 NM_006941.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.74
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16784614).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SOX10	NM_006941.4	MANE Select	c.1090C>A	p.Gln364Lys	missense	Exon 4 of 4	NP_008872.1	P56693-1
	POLR2F	NM_001301130.2		c.293+6636G>T		intron	N/A	NP_001288059.1	B0QYL9
	POLR2F	NM_001363825.1		c.*38+1496G>T		intron	N/A	NP_001350754.1	F8WC47

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SOX10	ENST00000396884.8	TSL:1 MANE Select	c.1090C>A	p.Gln364Lys	missense	Exon 4 of 4	ENSP00000380093.2	P56693-1
	SOX10	ENST00000360880.6	TSL:1	c.1090C>A	p.Gln364Lys	missense	Exon 5 of 5	ENSP00000354130.2	P56693-1
	SOX10	ENST00000698177.1		c.1306C>A	p.Gln436Lys	missense	Exon 5 of 5	ENSP00000513596.1	A0A8V8TM01

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.92e-7 AC: 1 AN: 1444128 Hom.: 0 Cov.: 31 AF XY: 0.00000140 AC XY: 1 AN XY: 715470

African (AFR) AF: 0.00 AC: 0 AN: 32860

American (AMR) AF: 0.00 AC: 0 AN: 43250

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25466

East Asian (EAS) AF: 0.00 AC: 0 AN: 39362

South Asian (SAS) AF: 0.0000117 AC: 1 AN: 85298

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52064

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5654

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1100756

Other (OTH) AF: 0.00 AC: 0 AN: 59418

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.064	T
BayesDel_noAF	Benign	-0.33
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.29	T
Eigen	Benign	0.0052
Eigen_PC	Benign	0.21
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.050	D
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-0.52	T
MutationAssessor	Benign	0.0	N
PhyloP100		8.7
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-0.39	N
REVEL	Benign	0.27
Sift	Benign	0.055	T
Sift4G	Benign	0.084	T
Polyphen		0.016	B
Vest4		0.11
MutPred		0.23		Gain of ubiquitination at Q364 (P = 0.0011)
MVP		0.72
MPC		1.0
ClinPred		0.65	D
GERP RS		4.9
Varity_R		0.16
gMVP		0.36
Mutation Taster		=73/27	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: rs1555937400; hg19: chr22-38369813;