Genetic Variant CHRNA3:p.Val53Val (chr15-78618839-T-C) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000743.5(CHRNA3):c.159A>G(p.Val53Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.379 in 1,613,816 control chromosomes in the GnomAD database, including 117,850 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.37 ( 10647 hom., cov: 33)

Exomes 𝑓: 0.38 ( 107203 hom. )

Consequence

CHRNA3
NM_000743.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -0.197

Publications

121 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.66).

BP6

Variant 15-78618839-T-C is Benign according to our data. Variant chr15-78618839-T-C is described in ClinVar as Benign. ClinVar VariationId is 1209688.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.197 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.401 is higher than 0.05.

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.159A>G	p.Val53Val	synonymous	Exon 2 of 6	NP_000734.2
CHRNA3	NM_001166694.2		c.159A>G	p.Val53Val	synonymous	Exon 2 of 6	NP_001160166.1
CHRNA3	NR_046313.2		n.361A>G		non_coding_transcript_exon	Exon 2 of 8

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CHRNA3	ENST00000326828.6	TSL:1 MANE Select	c.159A>G	p.Val53Val	synonymous	Exon 2 of 6	ENSP00000315602.5
CHRNA3	ENST00000348639.7	TSL:1	c.159A>G	p.Val53Val	synonymous	Exon 2 of 6	ENSP00000267951.4
CHRNA3	ENST00000559658.5	TSL:2	n.159A>G		non_coding_transcript_exon	Exon 2 of 8	ENSP00000452896.1

Frequencies

GnomAD3 genomes

AF:

0.371

AC:

56346

AN:

152044

Hom.:

10641

Cov.:

show subpopulations

Gnomad AFR

AF:

0.340

Gnomad AMI

AF:

0.442

Gnomad AMR

AF:

0.321

Gnomad ASJ

AF:

0.424

Gnomad EAS

AF:

0.347

Gnomad SAS

AF:

0.259

Gnomad FIN

AF:

0.374

Gnomad MID

AF:

0.453

Gnomad NFE

AF:

0.405

Gnomad OTH

AF:

0.393

GnomAD2 exomes

AF:

0.353

AC:

88657

AN:

251302

AF XY:

0.357

show subpopulations

Gnomad AFR exome

AF:

0.340

Gnomad AMR exome

AF:

0.224

Gnomad ASJ exome

AF:

0.427

Gnomad EAS exome

AF:

0.364

Gnomad FIN exome

AF:

0.372

Gnomad NFE exome

AF:

0.404

Gnomad OTH exome

AF:

0.363

GnomAD4 exome

AF:

0.380

AC:

555700

AN:

1461654

Hom.:

107203

Cov.:

AF XY:

0.378

AC XY:

274522

AN XY:

727122

show subpopulations

African (AFR)

AF:

0.343

AC:

11491

AN:

33478

American (AMR)

AF:

0.237

AC:

10590

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.425

AC:

11108

AN:

26136

East Asian (EAS)

AF:

0.355

AC:

14090

AN:

39698

South Asian (SAS)

AF:

0.271

AC:

23385

AN:

86252

European-Finnish (FIN)

AF:

0.379

AC:

20214

AN:

53326

Middle Eastern (MID)

AF:

0.435

AC:

2508

AN:

5760

European-Non Finnish (NFE)

AF:

0.395

AC:

439725

AN:

1111896

Other (OTH)

AF:

0.374

AC:

22589

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

20209

40418

60627

80836

101045

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

13502

27004

40506

54008

67510

<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:

0.371

AC:

56389

AN:

152162

Hom.:

10647

Cov.:

AF XY:

0.367

AC XY:

27285

AN XY:

74390

show subpopulations

African (AFR)

AF:

0.340

AC:

14100

AN:

41512

American (AMR)

AF:

0.321

AC:

4914

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.424

AC:

1472

AN:

3470

East Asian (EAS)

AF:

0.347

AC:

1797

AN:

5174

South Asian (SAS)

AF:

0.261

AC:

1256

AN:

4816

European-Finnish (FIN)

AF:

0.374

AC:

3956

AN:

10586

Middle Eastern (MID)

AF:

0.446

AC:

131

AN:

294

European-Non Finnish (NFE)

AF:

0.405

AC:

27540

AN:

67992

Other (OTH)

AF:

0.389

AC:

821

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.511

Heterozygous variant carriers

1887

3774

5660

7547

9434

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

540

1080

1620

2160

2700

<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:

0.383

Hom.:

37796

Bravo

AF:

0.365

Asia WGS

AF:

0.260

AC:

909

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Urinary bladder, atony of

Benign:1

Jul 22, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.66

CADD

Benign

(source)

DANN

Benign

0.65

PhyloP100

-0.20

PromoterAI

0.0050

Neutral

(source)

Mutation Taster

=99/1

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over