Genetic Variant CHRNA3:c.83-746C>G (chr15-78619661-G-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_000743.5(CHRNA3):c.83-746C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.65 in 151,488 control chromosomes in the GnomAD database, including 32,595 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.65 ( 32560 hom., cov: 28)

Exomes 𝑓: 0.58 ( 35 hom. )

Consequence

CHRNA3
NM_000743.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.33

Publications

24 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 -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.88).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.797 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein
CHRNA3	NM_000743.5 link	c.83-746C>G	intron_variant	Intron 1 of 5	ENST00000326828.6	NP_000734.2
CHRNA3	NM_001166694.2 link	c.83-746C>G	intron_variant	Intron 1 of 5		NP_001160166.1
CHRNA3	NR_046313.2 link	n.285-746C>G	intron_variant	Intron 1 of 7
CHRNA3	XM_006720382.4 link	c.-120+76C>G	intron_variant	Intron 1 of 5		XP_006720445.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHRNA3	ENST00000326828.6 link	c.83-746C>G		intron_variant	Intron 1 of 5	1	NM_000743.5	ENSP00000315602.5

Frequencies

GnomAD3 genomes

AF:

0.650

AC:

98323

AN:

151190

Hom.:

32512

Cov.:

show subpopulations

Gnomad AFR

AF:

0.728

Gnomad AMI

AF:

0.584

Gnomad AMR

AF:

0.742

Gnomad ASJ

AF:

0.634

Gnomad EAS

AF:

0.817

Gnomad SAS

AF:

0.675

Gnomad FIN

AF:

0.622

Gnomad MID

AF:

0.769

Gnomad NFE

AF:

0.574

Gnomad OTH

AF:

0.663

GnomAD4 exome

AF:

0.578

AC:

104

AN:

180

Hom.:

AF XY:

0.617

AC XY:

AN XY:

120

show subpopulations

African (AFR)

AF:

1.00

AC:

AN:

American (AMR)

AF:

0.400

AC:

AN:

Ashkenazi Jewish (ASJ)

AF:

0.500

AC:

AN:

East Asian (EAS)

AF:

1.00

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AF:

1.00

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.542

AC:

AN:

142

Other (OTH)

AF:

0.667

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.519

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<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:

0.651

AC:

98434

AN:

151308

Hom.:

32560

Cov.:

AF XY:

0.655

AC XY:

48374

AN XY:

73876

show subpopulations

African (AFR)

AF:

0.728

AC:

29998

AN:

41218

American (AMR)

AF:

0.743

AC:

11267

AN:

15166

Ashkenazi Jewish (ASJ)

AF:

0.634

AC:

2195

AN:

3460

East Asian (EAS)

AF:

0.818

AC:

4200

AN:

5136

South Asian (SAS)

AF:

0.676

AC:

3231

AN:

4778

European-Finnish (FIN)

AF:

0.622

AC:

6494

AN:

10446

Middle Eastern (MID)

AF:

0.762

AC:

224

AN:

294

European-Non Finnish (NFE)

AF:

0.574

AC:

38891

AN:

67800

Other (OTH)

AF:

0.668

AC:

1404

AN:

2102

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1644

3288

4933

6577

8221

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

778

1556

2334

3112

3890

<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:

0.610

Hom.:

3573

Bravo

AF:

0.664

Asia WGS

AF:

0.734

AC:

2553

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.88

CADD

Benign

1.1

(source)

DANN

Benign

0.35

PhyloP100

-1.3

PromoterAI

-0.0085

Neutral

(source)

Mutation Taster

=100/0

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

Computational scores

Splicing

Publications

Other links and lift over