Genetic Variant CHRNA3:c.268-64C>A (chr15-78617197-G-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000743.5(CHRNA3):c.268-64C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.619 in 1,084,310 control chromosomes in the GnomAD database, including 210,107 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.61 ( 28919 hom., cov: 32)

Exomes 𝑓: 0.62 ( 181188 hom. )

Consequence

CHRNA3
NM_000743.5 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -1.10

Publications

34 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: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.91).

BP6

Variant 15-78617197-G-T is Benign according to our data. Variant chr15-78617197-G-T is described in ClinVar as Benign. ClinVar VariationId is 1209769.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.734 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	Effect	Exon Rank	Protein	UniProt
CHRNA3	NM_000743.5	MANE Select	c.268-64C>A	intron	N/A	NP_000734.2
CHRNA3	NM_001166694.2		c.268-64C>A	intron	N/A	NP_001160166.1	P32297-3
CHRNA3	NR_046313.2		n.470-64C>A	intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
CHRNA3	ENST00000326828.6	TSL:1 MANE Select	c.268-64C>A	intron	N/A	ENSP00000315602.5	P32297-2
CHRNA3	ENST00000348639.7	TSL:1	c.268-64C>A	intron	N/A	ENSP00000267951.4	P32297-3
CHRNA3	ENST00000893003.1		c.400-64C>A	intron	N/A	ENSP00000563062.1

Frequencies

GnomAD3 genomes

AF:

0.612

AC:

92945

AN:

151822

Hom.:

28879

Cov.:

show subpopulations

Gnomad AFR

AF:

0.523

Gnomad AMI

AF:

0.586

Gnomad AMR

AF:

0.745

Gnomad ASJ

AF:

0.638

Gnomad EAS

AF:

0.559

Gnomad SAS

AF:

0.674

Gnomad FIN

AF:

0.651

Gnomad MID

AF:

0.788

Gnomad NFE

AF:

0.627

Gnomad OTH

AF:

0.642

GnomAD4 exome

AF:

0.620

AC:

577958

AN:

932368

Hom.:

181188

AF XY:

0.622

AC XY:

298227

AN XY:

479542

show subpopulations

African (AFR)

AF:

0.519

AC:

12250

AN:

23598

American (AMR)

AF:

0.816

AC:

29774

AN:

36478

Ashkenazi Jewish (ASJ)

AF:

0.636

AC:

13564

AN:

21318

East Asian (EAS)

AF:

0.569

AC:

20506

AN:

36028

South Asian (SAS)

AF:

0.681

AC:

47388

AN:

69590

European-Finnish (FIN)

AF:

0.651

AC:

30336

AN:

46624

Middle Eastern (MID)

AF:

0.714

AC:

3337

AN:

4674

European-Non Finnish (NFE)

AF:

0.605

AC:

394181

AN:

651080

Other (OTH)

AF:

0.619

AC:

26622

AN:

42978

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

9842

19684

29526

39368

49210

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

8304

16608

24912

33216

41520

<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:

0.612

AC:

93029

AN:

151942

Hom.:

28919

Cov.:

AF XY:

0.614

AC XY:

45630

AN XY:

74272

show subpopulations

African (AFR)

AF:

0.523

AC:

21662

AN:

41404

American (AMR)

AF:

0.746

AC:

11397

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.638

AC:

2211

AN:

3466

East Asian (EAS)

AF:

0.559

AC:

2873

AN:

5142

South Asian (SAS)

AF:

0.675

AC:

3259

AN:

4826

European-Finnish (FIN)

AF:

0.651

AC:

6871

AN:

10554

Middle Eastern (MID)

AF:

0.776

AC:

228

AN:

294

European-Non Finnish (NFE)

AF:

0.627

AC:

42632

AN:

67954

Other (OTH)

AF:

0.647

AC:

1363

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1842

3685

5527

7370

9212

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

762

1524

2286

3048

3810

<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:

0.607

Hom.:

3242

Bravo

AF:

0.614

Asia WGS

AF:

0.635

AC:

2209

AN:

3476

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Urinary bladder, atony of (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.91

CADD

Benign

0.44

(source)

DANN

Benign

0.73

PhyloP100

-1.1

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over