15-78601473-C-G

Position:

chr15-78601473-C-G

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBS1_Supporting

The NM_000743.5(CHRNA3):c.1169G>C(p.Gly390Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000248 in 1,614,108 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00017 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000096 ( 0 hom. )

Consequence

CHRNA3
NM_000743.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.312

Variant links:

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]

CHRNA3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.06683755).

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000171 (26/152218) while in subpopulation AFR AF= 0.000578 (24/41532). AF 95% confidence interval is 0.000398. There are 0 homozygotes in gnomad4. There are 15 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
CHRNA3	NM_000743.5 linkuse as main transcript	c.1169G>C	p.Gly390Ala	missense_variant	5/6	ENST00000326828.6	NP_000734.2
CHRNA3	NM_001166694.2 linkuse as main transcript	c.1169G>C	p.Gly390Ala	missense_variant	5/6		NP_001160166.1
CHRNA3	XM_006720382.4 linkuse as main transcript	c.968G>C	p.Gly323Ala	missense_variant	5/6		XP_006720445.1
CHRNA3	NR_046313.2 linkuse as main transcript	n.1371G>C		non_coding_transcript_exon_variant	5/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHRNA3	ENST00000326828.6 linkuse as main transcript	c.1169G>C	p.Gly390Ala	missense_variant	5/6	1	NM_000743.5	ENSP00000315602	P1	P32297-2
CHRNA3	ENST00000348639.7 linkuse as main transcript	c.1169G>C	p.Gly390Ala	missense_variant	5/6	1		ENSP00000267951		P32297-3
CHRNA3	ENST00000559658.5 linkuse as main transcript	c.1169G>C	p.Gly390Ala	missense_variant, NMD_transcript_variant	5/8	2		ENSP00000452896		P32297-2

Frequencies

GnomAD3 genomes

AF:

0.000158

AC:

AN:

152100

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000531

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.000480

GnomAD3 exomes

AF:

0.0000199

AC:

AN:

251328

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135836

show subpopulations

Gnomad AFR exome

AF:

0.000308

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000958

AC:

AN:

1461890

Hom.:

Cov.:

AF XY:

0.00000825

AC XY:

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.000358

Gnomad4 AMR exome

AF:

0.00

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:

0.0000331

GnomAD4 genome

AF:

0.000171

AC:

AN:

152218

Hom.:

Cov.:

AF XY:

0.000202

AC XY:

AN XY:

74416

show subpopulations

Gnomad4 AFR

AF:

0.000578

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.000475

Alfa

AF:

0.000214

Hom.:

Bravo

AF:

0.0000907

ESP6500AA

AF:

0.000455

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000330

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 26, 2022

The c.1169G>C (p.G390A) alteration is located in exon 5 (coding exon 5) of the CHRNA3 gene. This alteration results from a G to C substitution at nucleotide position 1169, causing the glycine (G) at amino acid position 390 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.080

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.29

CADD

Benign

4.7

DANN

Benign

0.82

DEOGEN2

Benign

0.26

.;T

Eigen

Benign

-0.77

Eigen_PC

Benign

-0.61

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.51

T;T

M_CAP

Benign

0.022

MetaRNN

Benign

0.067

T;T

MetaSVM

Benign

-0.87

MutationAssessor

Benign

1.1

L;L

MutationTaster

Benign

0.81

N;N

PrimateAI

Benign

0.27

PROVEAN

Benign

0.30

N;N

REVEL

Benign

0.20

Sift

Benign

0.38

T;T

Sift4G

Benign

0.27

T;T

Polyphen

0.0030

B;B

Vest4

0.12

MVP

0.80

MPC

0.28

ClinPred

0.0096

GERP RS

1.9

Varity_R

0.036

gMVP

0.29

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over