15-78601399-A-C

Position:

• chr15-78601399-A-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_000743.5(CHRNA3):​c.1243T>G​(p.Phe415Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000429 in 1,614,012 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.00049 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00042 (4 hom.)
• Consequence: CHRNA3 NM_000743.5 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.34

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0056548417).
• BP6: Variant 15-78601399-A-C is Benign according to our data. Variant chr15-78601399-A-C is described in ClinVar as [Benign]. Clinvar id is 736331.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.000423 (618/1461894) while in subpopulation AMR AF= 0.000894 (40/44724). AF 95% confidence interval is 0.000675. There are 4 homozygotes in gnomad4_exome. There are 292 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHRNA3	NM_000743.5	c.1243T>G	p.Phe415Val	missense_variant	5/6	ENST00000326828.6	NP_000734.2
CHRNA3	NM_001166694.2	c.1243T>G	p.Phe415Val	missense_variant	5/6		NP_001160166.1
CHRNA3	XM_006720382.4	c.1042T>G	p.Phe348Val	missense_variant	5/6		XP_006720445.1
CHRNA3	NR_046313.2	n.1445T>G		non_coding_transcript_exon_variant	5/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHRNA3	ENST00000326828.6	c.1243T>G	p.Phe415Val	missense_variant	5/6	1	NM_000743.5	ENSP00000315602	P1
CHRNA3	ENST00000348639.7	c.1243T>G	p.Phe415Val	missense_variant	5/6	1		ENSP00000267951
CHRNA3	ENST00000559658.5	c.1243T>G	p.Phe415Val	missense_variant, NMD_transcript_variant	5/8	2		ENSP00000452896

Frequencies

GnomAD3 genomes AF: 0.000493 AC: 75 AN: 152118 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.0170

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.000871 AC: 219 AN: 251442 Hom.: 1 AF XY: 0.000905 AC XY: 123 AN XY: 135898

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000954

Gnomad ASJ exome AF: 0.0148

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000229

Gnomad OTH exome AF: 0.00179

GnomAD4 exome AF: 0.000423 AC: 618 AN: 1461894 Hom.: 4 Cov.: 31 AF XY: 0.000402 AC XY: 292 AN XY: 727248

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000894

Gnomad4 ASJ exome AF: 0.0158

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000845

Gnomad4 OTH exome AF: 0.00116

GnomAD4 genome AF: 0.000493 AC: 75 AN: 152118 Hom.: 0 Cov.: 31 AF XY: 0.000417 AC XY: 31 AN XY: 74304

Gnomad4 AFR AF: 0.0000966

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.0170

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00191

Alfa AF: 0.00103 Hom.: 7

Bravo AF: 0.000491

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000699 AC: 6

ExAC AF: 0.000692 AC: 84

EpiCase AF: 0.000491

EpiControl AF: 0.000356

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 13, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.059
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	21
DANN	Benign	0.92
DEOGEN2	Benign	0.26	.;T
Eigen	Benign	-0.20
Eigen_PC	Benign	-0.0029
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.66	T;T
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.0057	T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	-0.35	N;N
MutationTaster	Benign	1.0	N;N
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	0.32	N;N
REVEL	Benign	0.20
Sift	Benign	0.32	T;T
Sift4G	Benign	0.55	T;T
Polyphen		0.0040	B;B
Vest4		0.41
MVP		0.70
MPC		0.33
ClinPred		0.045	T
GERP RS		4.5
Varity_R		0.081
gMVP		0.47

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs74381441; hg19: chr15-78893741;