dbSNP rs55958820: CHRNA3:p.Ile209Ile (chr15-78602015-G-T) – ACMG Classification: Benign (-19 pts)

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The NM_000743.5(CHRNA3):c.627C>A(p.Ile209Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00886 in 1,613,436 control chromosomes in the GnomAD database, including 91 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0062 ( 7 hom., cov: 31)

Exomes 𝑓: 0.0091 ( 84 hom. )

Consequence

CHRNA3
NM_000743.5 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.09

Publications

10 publications found

Variant links:

COSMIC-nc: COSV58776157

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 -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.44).

BP6

Variant 15-78602015-G-T is Benign according to our data. Variant chr15-78602015-G-T is described in ClinVar as Benign. ClinVar VariationId is 779448.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=1.09 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00619 (942/152184) while in subpopulation NFE AF = 0.0107 (728/68010). AF 95% confidence interval is 0.0101. There are 7 homozygotes in GnomAd4. There are 398 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 7 AR gene

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	UniProt
CHRNA3	NM_000743.5	MANE Select	c.627C>A	p.Ile209Ile	synonymous	Exon 5 of 6	NP_000734.2
CHRNA3	NM_001166694.2		c.627C>A	p.Ile209Ile	synonymous	Exon 5 of 6	NP_001160166.1	P32297-3
CHRNA3	NR_046313.2		n.829C>A		non_coding_transcript_exon	Exon 5 of 8

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CHRNA3	ENST00000326828.6	TSL:1 MANE Select	c.627C>A	p.Ile209Ile	synonymous	Exon 5 of 6	ENSP00000315602.5	P32297-2
CHRNA3	ENST00000348639.7	TSL:1	c.627C>A	p.Ile209Ile	synonymous	Exon 5 of 6	ENSP00000267951.4	P32297-3
CHRNA3	ENST00000893003.1		c.759C>A	p.Ile253Ile	synonymous	Exon 6 of 7	ENSP00000563062.1

Frequencies

GnomAD3 genomes

AF:

0.00617

AC:

939

AN:

152066

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00162

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00721

Gnomad ASJ

AF:

0.000865

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00104

Gnomad FIN

AF:

0.00141

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0107

Gnomad OTH

AF:

0.00621

GnomAD2 exomes

AF:

0.00598

AC:

1502

AN:

251354

AF XY:

0.00616

show subpopulations

Gnomad AFR exome

AF:

0.00154

Gnomad AMR exome

AF:

0.00353

Gnomad ASJ exome

AF:

0.000199

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00139

Gnomad NFE exome

AF:

0.0110

Gnomad OTH exome

AF:

0.00375

GnomAD4 exome

AF:

0.00913

AC:

13347

AN:

1461252

Hom.:

Cov.:

AF XY:

0.00897

AC XY:

6520

AN XY:

726784

show subpopulations

African (AFR)

AF:

0.00146

AC:

AN:

33470

American (AMR)

AF:

0.00387

AC:

173

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.000727

AC:

AN:

26124

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39688

South Asian (SAS)

AF:

0.00190

AC:

164

AN:

86248

European-Finnish (FIN)

AF:

0.00200

AC:

107

AN:

53418

Middle Eastern (MID)

AF:

0.00139

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0111

AC:

12367

AN:

1111450

Other (OTH)

AF:

0.00759

AC:

458

AN:

60370

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.456

Heterozygous variant carriers

771

1541

2312

3082

3853

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

468

936

1404

1872

2340

<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:

0.00619

AC:

942

AN:

152184

Hom.:

Cov.:

AF XY:

0.00535

AC XY:

398

AN XY:

74422

show subpopulations

African (AFR)

AF:

0.00161

AC:

AN:

41522

American (AMR)

AF:

0.00720

AC:

110

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.000865

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5168

South Asian (SAS)

AF:

0.00125

AC:

AN:

4800

European-Finnish (FIN)

AF:

0.00141

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0107

AC:

728

AN:

68010

Other (OTH)

AF:

0.00614

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

100

150

200

250

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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

Alfa

AF:

0.00662

Hom.:

Bravo

AF:

0.00621

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00807

EpiControl

AF:

0.0101

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.44

CADD

Benign

9.6

(source)

DANN

Benign

0.82

PhyloP100

1.1

Mutation Taster

=99/1

polymorphism

(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