15-78601383-G-A

Position:

chr15-78601383-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 2P and 10B. PM2BP4_StrongBP6_ModerateBS1

The NM_000743.5(CHRNA3):c.1259C>T(p.Thr420Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000151 in 1,614,190 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00015 ( 0 hom. )

Consequence

CHRNA3
NM_000743.5 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 3.46

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 Benign. Variant got -8 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.0165523).

BP6

Variant 15-78601383-G-A is Benign according to our data. Variant chr15-78601383-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 2083191.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000138 (21/152296) while in subpopulation AMR AF= 0.00105 (16/15290). AF 95% confidence interval is 0.000656. There are 0 homozygotes in gnomad4. There are 10 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
CHRNA3	NM_000743.5 linkuse as main transcript	c.1259C>T	p.Thr420Met	missense_variant	5/6	ENST00000326828.6	NP_000734.2
CHRNA3	NM_001166694.2 linkuse as main transcript	c.1259C>T	p.Thr420Met	missense_variant	5/6		NP_001160166.1
CHRNA3	XM_006720382.4 linkuse as main transcript	c.1058C>T	p.Thr353Met	missense_variant	5/6		XP_006720445.1
CHRNA3	NR_046313.2 linkuse as main transcript	n.1461C>T		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.1259C>T	p.Thr420Met	missense_variant	5/6	1	NM_000743.5	ENSP00000315602	P1	P32297-2
CHRNA3	ENST00000348639.7 linkuse as main transcript	c.1259C>T	p.Thr420Met	missense_variant	5/6	1		ENSP00000267951		P32297-3
CHRNA3	ENST00000559658.5 linkuse as main transcript	c.1259C>T	p.Thr420Met	missense_variant, NMD_transcript_variant	5/8	2		ENSP00000452896		P32297-2

Frequencies

GnomAD3 genomes

AF:

0.000138

AC:

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00105

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000485

AC:

122

AN:

251442

Hom.:

AF XY:

0.000412

AC XY:

AN XY:

135890

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00295

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000425

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000440

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000153

AC:

223

AN:

1461894

Hom.:

Cov.:

AF XY:

0.000149

AC XY:

108

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00259

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000475

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000549

Gnomad4 OTH exome

AF:

0.0000662

GnomAD4 genome

AF:

0.000138

AC:

AN:

152296

Hom.:

Cov.:

AF XY:

0.000134

AC XY:

AN XY:

74470

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00105

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000111

Hom.:

Bravo

AF:

0.000170

ExAC

AF:

0.000387

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 29, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.089

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.12

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.44

.;T

Eigen

Uncertain

0.55

Eigen_PC

Uncertain

0.60

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.75

T;T

M_CAP

Benign

0.052

MetaRNN

Benign

0.017

T;T

MetaSVM

Uncertain

-0.088

MutationAssessor

Benign

1.5

L;L

MutationTaster

Benign

0.89

N;N

PrimateAI

Benign

0.40

PROVEAN

Benign

-0.81

N;N

REVEL

Uncertain

0.38

Sift

Benign

0.11

T;T

Sift4G

Benign

0.17

T;T

Polyphen

0.99

D;P

Vest4

0.20

MVP

0.90

MPC

0.81

ClinPred

0.069

GERP RS

5.8

Varity_R

0.048

gMVP

0.32

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