15-78617072-C-T

Position:

• chr15-78617072-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Moderate BS1

The NM_000743.5(CHRNA3):​c.329G>A​(p.Arg110His) variant causes a missense change. The variant allele was found at a frequency of 0.000301 in 1,613,918 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00028 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00030 (0 hom.)
• Consequence: CHRNA3 NM_000743.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.13

Genes affected

CHRNA3 (HGNC:1957): (cholinergic receptor nicotinic alpha 3 subunit) This locus encodes a member of the nicotinic acetylcholine receptor family of proteins. Members of this family of proteins form pentameric complexes comprised of both alpha and beta subunits. This locus encodes an alpha-type subunit, as it contains characteristic adjacent cysteine residues. The encoded protein is a ligand-gated ion channel that likely plays a role in neurotransmission. Polymorphisms in this gene have been associated with an increased risk of smoking initiation and an increased susceptibility to lung cancer. Alternatively spliced transcript variants have been described. [provided by RefSeq, Nov 2009]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.11771971).
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000282 (43/152320) while in subpopulation AMR AF= 0.000523 (8/15292). AF 95% confidence interval is 0.000304. There are 0 homozygotes in gnomad4. There are 21 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHRNA3	NM_000743.5	c.329G>A	p.Arg110His	missense_variant	4/6	ENST00000326828.6	NP_000734.2
CHRNA3	NM_001166694.2	c.329G>A	p.Arg110His	missense_variant	4/6		NP_001160166.1
CHRNA3	XM_006720382.4	c.128G>A	p.Arg43His	missense_variant	4/6		XP_006720445.1
CHRNA3	NR_046313.2	n.531G>A		non_coding_transcript_exon_variant	4/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHRNA3	ENST00000326828.6	c.329G>A	p.Arg110His	missense_variant	4/6	1	NM_000743.5	ENSP00000315602	P1
CHRNA3	ENST00000348639.7	c.329G>A	p.Arg110His	missense_variant	4/6	1		ENSP00000267951
CHRNA3	ENST00000559658.5	c.329G>A	p.Arg110His	missense_variant, NMD_transcript_variant	4/8	2		ENSP00000452896

Frequencies

GnomAD3 genomes AF: 0.000283 AC: 43 AN: 152202 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000524

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000426

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000255 AC: 64 AN: 251070 Hom.: 0 AF XY: 0.000221 AC XY: 30 AN XY: 135720

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.000596

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0000981

Gnomad FIN exome AF: 0.0000930

Gnomad NFE exome AF: 0.000422

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000303 AC: 443 AN: 1461598 Hom.: 0 Cov.: 30 AF XY: 0.000268 AC XY: 195 AN XY: 727108

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.000421

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000812

Gnomad4 FIN exome AF: 0.0000563

Gnomad4 NFE exome AF: 0.000367

Gnomad4 OTH exome AF: 0.000116

GnomAD4 genome AF: 0.000282 AC: 43 AN: 152320 Hom.: 0 Cov.: 32 AF XY: 0.000282 AC XY: 21 AN XY: 74474

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.000523

Gnomad4 ASJ AF: 0.000864

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000426

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000440 Hom.: 0

Bravo AF: 0.000351

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000582 AC: 5

ExAC AF: 0.000296 AC: 36

EpiCase AF: 0.000600

EpiControl AF: 0.000237

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Uncertain	0.013	T
BayesDel_noAF	Uncertain	0.10
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.78	.;D
Eigen	Benign	0.14
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.89	D;D
M_CAP	Benign	0.056	D
MetaRNN	Benign	0.12	T;T
MetaSVM	Benign	-0.32	T
MutationAssessor	Benign	1.9	L;L
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.36	T
PROVEAN	Uncertain	-4.2	D;D
REVEL	Uncertain	0.57
Sift	Benign	0.31	T;T
Sift4G	Benign	0.18	T;T
Polyphen		0.24	B;B
Vest4		0.29
MVP		0.83
MPC		0.34
ClinPred		0.36	T
GERP RS		4.7
Varity_R		0.28
gMVP		0.50

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: rs77574318; hg19: chr15-78909414; COSMIC: COSV100468111; COSMIC: COSV100468111;