chr15-78596440-A-AT

Variant names:

• chr15-78596440-A-AT
• rs71148543
• NM_000743.5:c.*163dupA

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1 BS2

The NM_000743.5(CHRNA3):​c.*163dupA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00087 (0 hom., cov: 0)
  • Exomes 𝑓: 0.0073 (2 hom.)
• Consequence: CHRNA3 NM_000743.5 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.998
• Publications: 2 publications found

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

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000873 (131/149986) while in subpopulation NFE AF = 0.00104 (70/67270). AF 95% confidence interval is 0.000844. There are 0 homozygotes in GnomAd4. There are 59 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHRNA3	NM_000743.5	c.*163dupA		3_prime_UTR_variant	Exon 6 of 6	ENST00000326828.6	NP_000734.2
CHRNA3	XM_006720382.4	c.*163dupA		3_prime_UTR_variant	Exon 6 of 6		XP_006720445.1
CHRNA3	NM_001166694.2	c.1390-3250dupA		intron_variant	Intron 5 of 5		NP_001160166.1
CHRNA3	NR_046313.2	n.1784+99dupA		intron_variant	Intron 6 of 7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHRNA3	ENST00000326828.6	c.*163dupA		3_prime_UTR_variant	Exon 6 of 6	1	NM_000743.5	ENSP00000315602.5
CHRNA3	ENST00000348639.7	c.1390-3250dupA		intron_variant	Intron 5 of 5	1		ENSP00000267951.4
CHRNA3	ENST00000559002.5	n.193+99dupA		intron_variant	Intron 1 of 1	1
CHRNA3	ENST00000559658.5	n.*64+99dupA		intron_variant	Intron 6 of 7	2		ENSP00000452896.1

Frequencies

GnomAD3 genomes AF: 0.000874 AC: 131 AN: 149880 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000880

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000664

Gnomad ASJ AF: 0.000581

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.000841

Gnomad FIN AF: 0.000200

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00104

Gnomad OTH AF: 0.00243

GnomAD4 exome AF: 0.00727 AC: 6872 AN: 944894 Hom.: 2 Cov.: 0 AF XY: 0.00742 AC XY: 3338 AN XY: 449906

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00422 AC: 90 AN: 21336

American (AMR) AF: 0.00707 AC: 65 AN: 9192

Ashkenazi Jewish (ASJ) AF: 0.0117 AC: 149 AN: 12778

East Asian (EAS) AF: 0.00245 AC: 51 AN: 20858

South Asian (SAS) AF: 0.00727 AC: 207 AN: 28462

European-Finnish (FIN) AF: 0.0142 AC: 290 AN: 20388

Middle Eastern (MID) AF: 0.0114 AC: 30 AN: 2628

European-Non Finnish (NFE) AF: 0.00715 AC: 5647 AN: 790216

Other (OTH) AF: 0.00879 AC: 343 AN: 39036

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.000873 AC: 131 AN: 149986 Hom.: 0 Cov.: 0 AF XY: 0.000806 AC XY: 59 AN XY: 73198

African (AFR) AF: 0.000878 AC: 36 AN: 41018

American (AMR) AF: 0.000663 AC: 10 AN: 15082

Ashkenazi Jewish (ASJ) AF: 0.000581 AC: 2 AN: 3444

East Asian (EAS) AF: 0.000195 AC: 1 AN: 5134

South Asian (SAS) AF: 0.000842 AC: 4 AN: 4752

European-Finnish (FIN) AF: 0.000200 AC: 2 AN: 10008

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00104 AC: 70 AN: 67270

Other (OTH) AF: 0.00240 AC: 5 AN: 2080

Alfa AF: 0.00 Hom.: 256

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-1.0
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs71148543; hg19: chr15-78888782;