Genetic Variant NM_000743.5:c.291A>T (chr15-78617110-T-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_000743.5(CHRNA3):c.291A>T(p.Lys97Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. K97K) has been classified as Benign.

Frequency

Genomes: not found (cov: 32)

Consequence

CHRNA3
NM_000743.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.731

Publications

54 publications found

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 Gene-Disease associations (from GenCC):

urinary bladder, atony of
Inheritance: AR Classification: STRONG Submitted by: Ambry Genetics, G2P

CHRNA3 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000743.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CHRNA3	NM_000743.5	MANE Select	c.291A>T	p.Lys97Asn	missense	Exon 4 of 6	NP_000734.2
CHRNA3	NM_001166694.2		c.291A>T	p.Lys97Asn	missense	Exon 4 of 6	NP_001160166.1
CHRNA3	NR_046313.2		n.493A>T		non_coding_transcript_exon	Exon 4 of 8

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CHRNA3	ENST00000326828.6	TSL:1 MANE Select	c.291A>T	p.Lys97Asn	missense	Exon 4 of 6	ENSP00000315602.5
CHRNA3	ENST00000348639.7	TSL:1	c.291A>T	p.Lys97Asn	missense	Exon 4 of 6	ENSP00000267951.4
CHRNA3	ENST00000559658.5	TSL:2	n.291A>T		non_coding_transcript_exon	Exon 4 of 8	ENSP00000452896.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000400

AC:

AN:

250308

AF XY:

0.00000739

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000883

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.53

BayesDel_addAF

Benign

-0.0097

BayesDel_noAF

Benign

-0.25

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.52

Eigen

Benign

-0.087

Eigen_PC

Benign

0.0099

FATHMM_MKL

Uncertain

0.84

LIST_S2

Uncertain

0.90

M_CAP

Benign

0.079

MetaRNN

Uncertain

0.68

MetaSVM

Uncertain

-0.24

MutationAssessor

Benign

1.6

PhyloP100

0.73

PrimateAI

Uncertain

0.65

PROVEAN

Benign

-1.9

REVEL

Uncertain

0.36

Sift

Uncertain

0.0040

Sift4G

Benign

0.063

Polyphen

0.65

Vest4

0.42

MutPred

0.61

Loss of ubiquitination at K97 (P = 0.0218)

MVP

0.76

MPC

0.56

ClinPred

0.78

GERP RS

4.8

Varity_R

0.49

gMVP

0.46

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over