15-78618888-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBA1

The NM_000743.5(CHRNA3):c.110G>A(p.Arg37His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0435 in 1,613,684 control chromosomes in the GnomAD database, including 1,825 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R37P) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.030 ( 102 hom., cov: 33)

Exomes 𝑓: 0.045 ( 1723 hom. )

Consequence

CHRNA3
NM_000743.5 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 2.65

Publications

45 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.011311233).

BP6

Variant 15-78618888-C-T is Benign according to our data. Variant chr15-78618888-C-T is described in ClinVar as Benign. ClinVar VariationId is 2020686.Status of the report is criteria_provided_single_submitter, 1 stars.

BA1

GnomAdExome4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0526 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
CHRNA3	NM_000743.5 link	c.110G>A	p.Arg37His	missense_variant	Exon 2 of 6	ENST00000326828.6	NP_000734.2
CHRNA3	NM_001166694.2 link	c.110G>A	p.Arg37His	missense_variant	Exon 2 of 6		NP_001160166.1
CHRNA3	NR_046313.2 link	n.312G>A		non_coding_transcript_exon_variant	Exon 2 of 8
CHRNA3	XM_006720382.4 link	c.-92G>A		5_prime_UTR_variant	Exon 2 of 6		XP_006720445.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHRNA3	ENST00000326828.6 link	c.110G>A	p.Arg37His	missense_variant	Exon 2 of 6	1	NM_000743.5	ENSP00000315602.5

Frequencies

GnomAD3 genomes

AF:

0.0304

AC:

4630

AN:

152184

Hom.:

102

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0113

Gnomad AMI

AF:

0.00989

Gnomad AMR

AF:

0.0216

Gnomad ASJ

AF:

0.0173

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.0153

Gnomad FIN

AF:

0.0266

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.0491

Gnomad OTH

AF:

0.0291

GnomAD2 exomes

AF:

0.0293

AC:

7354

AN:

251366

AF XY:

0.0301

show subpopulations

Gnomad AFR exome

AF:

0.0108

Gnomad AMR exome

AF:

0.0144

Gnomad ASJ exome

AF:

0.0172

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.0290

Gnomad NFE exome

AF:

0.0459

Gnomad OTH exome

AF:

0.0323

GnomAD4 exome

AF:

0.0448

AC:

65514

AN:

1461382

Hom.:

1723

Cov.:

AF XY:

0.0438

AC XY:

31875

AN XY:

726990

show subpopulations

African (AFR)

AF:

0.0103

AC:

346

AN:

33468

American (AMR)

AF:

0.0150

AC:

672

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.0158

AC:

412

AN:

26134

East Asian (EAS)

AF:

0.0000756

AC:

AN:

39700

South Asian (SAS)

AF:

0.0160

AC:

1377

AN:

86240

European-Finnish (FIN)

AF:

0.0283

AC:

1509

AN:

53274

Middle Eastern (MID)

AF:

0.0252

AC:

140

AN:

5554

European-Non Finnish (NFE)

AF:

0.0530

AC:

58888

AN:

1111918

Other (OTH)

AF:

0.0359

AC:

2167

AN:

60374

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

3467

6934

10401

13868

17335

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2192

4384

6576

8768

10960

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0304

AC:

4631

AN:

152302

Hom.:

102

Cov.:

AF XY:

0.0288

AC XY:

2148

AN XY:

74480

show subpopulations

African (AFR)

AF:

0.0113

AC:

468

AN:

41576

American (AMR)

AF:

0.0216

AC:

330

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.0173

AC:

AN:

3468

East Asian (EAS)

AF:

0.000193

AC:

AN:

5172

South Asian (SAS)

AF:

0.0153

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.0266

AC:

282

AN:

10616

Middle Eastern (MID)

AF:

0.0204

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0491

AC:

3340

AN:

68020

Other (OTH)

AF:

0.0288

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

241

482

722

963

1204

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

112

168

224

280

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0412

Hom.:

648

Bravo

AF:

0.0294

TwinsUK

AF:

0.0566

AC:

210

ALSPAC

AF:

0.0573

AC:

221

ESP6500AA

AF:

0.0107

AC:

ESP6500EA

AF:

0.0518

AC:

445

ExAC

AF:

0.0291

AC:

3538

Asia WGS

AF:

0.00895

AC:

AN:

3478

EpiCase

AF:

0.0456

EpiControl

AF:

0.0438

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.23

CADD

Uncertain

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.83

.;D

Eigen

Uncertain

0.57

Eigen_PC

Uncertain

0.51

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.94

D;D

MetaRNN

Benign

0.011

T;T

MetaSVM

Uncertain

-0.10

MutationAssessor

Uncertain

2.8

M;M

PhyloP100

2.7

PrimateAI

Uncertain

0.63

PROVEAN

Uncertain

-3.7

D;D

REVEL

Uncertain

0.39

Sift

Uncertain

0.0010

D;D

Sift4G

Uncertain

0.022

D;D

Polyphen

0.97

D;D

Vest4

0.25

MPC

0.98

ClinPred

0.027

GERP RS

5.7

PromoterAI

-0.026

Neutral

(source)

Varity_R

0.42

gMVP

0.49

Mutation Taster

=92/8

polymorphism (auto)

(source)

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over