15-78601522-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS1

The NM_000743.5(CHRNA3):c.1120G>A(p.Gly374Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000199 in 1,614,126 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00046 (1 hom., cov: 31)
  • Exomes 𝑓: 0.00017 (4 hom.)
• Consequence: CHRNA3 NM_000743.5 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0430

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0076290667).
• BP6: Variant 15-78601522-C-T is Benign according to our data. Variant chr15-78601522-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 779961.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00046 (70/152234) while in subpopulation EAS AF= 0.00697 (36/5168). AF 95% confidence interval is 0.00517. There are 1 homozygotes in gnomad4. There are 31 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHRNA3	NM_000743.5	c.1120G>A	p.Gly374Ser	missense_variant	5/6	ENST00000326828.6
CHRNA3	NM_001166694.2	c.1120G>A	p.Gly374Ser	missense_variant	5/6
CHRNA3	XM_006720382.4	c.919G>A	p.Gly307Ser	missense_variant	5/6
CHRNA3	NR_046313.2	n.1322G>A		non_coding_transcript_exon_variant	5/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHRNA3	ENST00000326828.6	c.1120G>A	p.Gly374Ser	missense_variant	5/6	1	NM_000743.5	P1
CHRNA3	ENST00000348639.7	c.1120G>A	p.Gly374Ser	missense_variant	5/6	1
CHRNA3	ENST00000559658.5	c.1120G>A	p.Gly374Ser	missense_variant, NMD_transcript_variant	5/8	2

Frequencies

GnomAD3 genomes AF: 0.000454 AC: 69 AN: 152116 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.000676

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00695

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.000633 AC: 159 AN: 251248 Hom.: 0 AF XY: 0.000538 AC XY: 73 AN XY: 135798

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00783

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000652

GnomAD4 exome AF: 0.000172 AC: 251 AN: 1461892 Hom.: 4 Cov.: 31 AF XY: 0.000165 AC XY: 120 AN XY: 727246

Gnomad4 AFR exome AF: 0.000687

Gnomad4 AMR exome AF: 0.000179

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00277

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000144

Gnomad4 OTH exome AF: 0.00151

GnomAD4 genome AF: 0.000460 AC: 70 AN: 152234 Hom.: 1 Cov.: 31 AF XY: 0.000417 AC XY: 31 AN XY: 74428

Gnomad4 AFR AF: 0.000698

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00697

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.000334 Hom.: 0

Bravo AF: 0.000574

ESP6500AA AF: 0.000683 AC: 3

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000717 AC: 87

Asia WGS AF: 0.00664 AC: 23 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Oct 16, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.38
Cadd	Benign	1.8
Dann	Benign	0.45
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.0092	N
LIST_S2	Benign	0.67	T;T
M_CAP	Benign	0.063	D
MetaRNN	Benign	0.0076	T;T
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	0.51	N;N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.26	T
PROVEAN	Benign	0.50	N;N
REVEL	Benign	0.099
Sift	Benign	0.42	T;T
Sift4G	Benign	0.48	T;T
Polyphen		0.0040	B;B
Vest4		0.014
MVP		0.64
MPC		0.25
ClinPred		0.00053	T
GERP RS		-1.2
Varity_R		0.032
gMVP		0.22

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

LitVar

Other links and lift over

dbSNP: rs141141954; hg19: chr15-78893864; COSMIC: COSV58776091; COSMIC: COSV58776091;