dbSNP rs77574318: CHRNA3:p.Arg110His (chr15-78617072-C-T) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS1

The NM_000743.5(CHRNA3):c.329G>A(p.Arg110His) variant causes a missense change. The variant allele was found at a frequency of 0.000301 in 1,613,918 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.00028 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00030 ( 0 hom. )

Consequence

CHRNA3
NM_000743.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.13

Publications

5 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: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.11771971).

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000282 (43/152320) while in subpopulation AMR AF = 0.000523 (8/15292). AF 95% confidence interval is 0.000304. There are 0 homozygotes in GnomAd4. There are 21 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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.329G>A	p.Arg110His	missense	Exon 4 of 6	NP_000734.2
CHRNA3	NM_001166694.2		c.329G>A	p.Arg110His	missense	Exon 4 of 6	NP_001160166.1
CHRNA3	NR_046313.2		n.531G>A		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.329G>A	p.Arg110His	missense	Exon 4 of 6	ENSP00000315602.5
CHRNA3	ENST00000348639.7	TSL:1	c.329G>A	p.Arg110His	missense	Exon 4 of 6	ENSP00000267951.4
CHRNA3	ENST00000559658.5	TSL:2	n.329G>A		non_coding_transcript_exon	Exon 4 of 8	ENSP00000452896.1

Frequencies

GnomAD3 genomes

AF:

0.000283

AC:

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000524

Gnomad ASJ

AF:

0.000864

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000426

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000255

AC:

AN:

251070

AF XY:

0.000221

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.000596

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.0000930

Gnomad NFE exome

AF:

0.000422

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000303

AC:

443

AN:

1461598

Hom.:

Cov.:

AF XY:

0.000268

AC XY:

195

AN XY:

727108

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.000112

AC:

AN:

44708

Ashkenazi Jewish (ASJ)

AF:

0.000421

AC:

AN:

26130

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000812

AC:

AN:

86234

European-Finnish (FIN)

AF:

0.0000563

AC:

AN:

53296

Middle Eastern (MID)

AF:

0.000347

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.000367

AC:

408

AN:

1111902

Other (OTH)

AF:

0.000116

AC:

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

102

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<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:

0.000282

AC:

AN:

152320

Hom.:

Cov.:

AF XY:

0.000282

AC XY:

AN XY:

74474

show subpopulations

African (AFR)

AF:

0.0000481

AC:

AN:

41574

American (AMR)

AF:

0.000523

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.000864

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000426

AC:

AN:

68032

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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

Alfa

AF:

0.000401

Hom.:

Bravo

AF:

0.000351

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000582

AC:

ExAC

AF:

0.000296

AC:

EpiCase

AF:

0.000600

EpiControl

AF:

0.000237

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.25

BayesDel_addAF

Uncertain

0.013

BayesDel_noAF

Uncertain

0.10

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.78

Eigen

Benign

0.14

Eigen_PC

Uncertain

0.26

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.89

M_CAP

Benign

0.056

MetaRNN

Benign

0.12

MetaSVM

Benign

-0.32

MutationAssessor

Benign

1.9

PhyloP100

4.1

PrimateAI

Benign

0.36

PROVEAN

Uncertain

-4.2

REVEL

Uncertain

0.57

Sift

Benign

0.31

Sift4G

Benign

0.18

Polyphen

0.24

Vest4

0.29

MVP

0.83

MPC

0.34

ClinPred

0.36

GERP RS

4.7

Varity_R

0.28

gMVP

0.50

Mutation Taster

=40/60

disease causing

(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