chr11-3667268-C-T

Variant names:

• chr11-3667268-C-T
• rs769677015
• NM_020402.4:c.859G>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_020402.4(CHRNA10):​c.859G>A​(p.Glu287Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000097 in 1,443,010 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 (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000097 (0 hom.)
• Consequence: CHRNA10 NM_020402.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.79
• Publications: 0 publications found

Genes affected

CHRNA10 (HGNC:13800): (cholinergic receptor nicotinic alpha 10 subunit) Predicted to enable acetylcholine-gated cation-selective channel activity. Acts upstream of or within positive regulation of cytosolic calcium ion concentration. Predicted to be located in membrane. Predicted to be active in cholinergic synapse and neuron projection. Predicted to be integral component of postsynaptic specialization membrane. [provided by Alliance of Genome Resources, Apr 2022]

ART1 (HGNC:723): (ADP-ribosyltransferase 1) ADP-ribosyltransferase catalyzes the ADP-ribosylation of arginine residues in proteins. Mono-ADP-ribosylation is a posttranslational modification of proteins that is interfered with by a variety of bacterial toxins including cholera, pertussis, and heat-labile enterotoxins of E. coli. The amino acid sequence consists of predominantly hydrophobic N- and C-terminal regions, which is characteristic of glycosylphosphatidylinositol (GPI)-anchored proteins. This gene was previously designated ART2. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.921

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020402.4. 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
	CHRNA10	NM_020402.4	MANE Select	c.859G>A	p.Glu287Lys	missense	Exon 4 of 5	NP_065135.2
	CHRNA10	NM_001303034.2		c.241G>A	p.Glu81Lys	missense	Exon 4 of 5	NP_001289963.1
	CHRNA10	NM_001303035.2		c.241G>A	p.Glu81Lys	missense	Exon 4 of 5	NP_001289964.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHRNA10	ENST00000250699.2	TSL:1 MANE Select	c.859G>A	p.Glu287Lys	missense	Exon 4 of 5	ENSP00000250699.2	Q9GZZ6
	CHRNA10	ENST00000534359.1	TSL:1	c.312G>A	p.Pro104Pro	synonymous	Exon 4 of 5	ENSP00000437107.1	E9PNX2
	CHRNA10	ENST00000526599.1	TSL:1	n.*630G>A		non_coding_transcript_exon	Exon 4 of 5	ENSP00000432757.1	E9PNT7

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000317 AC: 7 AN: 220588 AF XY: 0.0000328

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000597

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000200

Gnomad OTH exome AF: 0.000178

GnomAD4 exome AF: 0.00000970 AC: 14 AN: 1443010 Hom.: 0 Cov.: 32 AF XY: 0.00000557 AC XY: 4 AN XY: 718162

African (AFR) AF: 0.00 AC: 0 AN: 33348

American (AMR) AF: 0.0000453 AC: 2 AN: 44158

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25968

East Asian (EAS) AF: 0.00 AC: 0 AN: 39500

South Asian (SAS) AF: 0.0000117 AC: 1 AN: 85816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38990

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5512

European-Non Finnish (NFE) AF: 0.00000721 AC: 8 AN: 1109742

Other (OTH) AF: 0.0000500 AC: 3 AN: 59976

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000167 AC: 2

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.78
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Pathogenic	0.20
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.53	D
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.97	D
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Uncertain	0.068	D
MutationAssessor	Benign	1.6	L
PhyloP100		7.8
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-4.0	D
REVEL	Pathogenic	0.76
Sift	Uncertain	0.0010	D
Sift4G	Benign	0.11	T
Polyphen		1.0	D
Vest4		0.92
MutPred		0.78		Gain of ubiquitination at E287 (P = 0.0177)
MVP		0.80
MPC		0.63
ClinPred		0.81	D
GERP RS		5.0
Varity_R		0.91
gMVP		0.72
Mutation Taster		=39/61	disease causing

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: rs769677015; hg19: chr11-3688498; COSMIC: COSV105860209; COSMIC: COSV105860209;