15-78596440-ATTT-AT

Variant names:

• chr15-78596440-ATT-A
• rs71148543
• NM_000743.5:c.*162_*163delAA

Variant summary

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

The NM_000743.5(CHRNA3):​c.*162_*163delAA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0012 in 1,120,818 control chromosomes in the GnomAD database, including 3 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00025 (1 hom., cov: 0)
  • Exomes 𝑓: 0.0013 (2 hom.)
• Consequence: CHRNA3 NM_000743.5 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.830
• 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 sas. GnomAd4 allele frequency = 0.000253 (38/149990) while in subpopulation SAS AF = 0.00568 (27/4752). AF 95% confidence interval is 0.00401. There are 1 homozygotes in GnomAd4. There are 26 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.*162_*163delAA		3_prime_UTR_variant	Exon 6 of 6	ENST00000326828.6	NP_000734.2
CHRNA3	XM_006720382.4	c.*162_*163delAA		3_prime_UTR_variant	Exon 6 of 6		XP_006720445.1
CHRNA3	NM_001166694.2	c.1390-3251_1390-3250delAA		intron_variant	Intron 5 of 5		NP_001160166.1
CHRNA3	NR_046313.2	n.1784+98_1784+99delAA		intron_variant	Intron 6 of 7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHRNA3	ENST00000326828.6	c.*162_*163delAA		3_prime_UTR_variant	Exon 6 of 6	1	NM_000743.5	ENSP00000315602.5
CHRNA3	ENST00000348639.7	c.1390-3251_1390-3250delAA		intron_variant	Intron 5 of 5	1		ENSP00000267951.4
CHRNA3	ENST00000559002.5	n.193+98_193+99delAA		intron_variant	Intron 1 of 1	1
CHRNA3	ENST00000559658.5	n.*64+98_*64+99delAA		intron_variant	Intron 6 of 7	2		ENSP00000452896.1

Frequencies

GnomAD3 genomes AF: 0.000260 AC: 39 AN: 149884 Hom.: 1 Cov.: 0

Gnomad AFR AF: 0.000122

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000664

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000583

Gnomad SAS AF: 0.00588

Gnomad FIN AF: 0.0000998

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000149

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00135 AC: 1308 AN: 970828 Hom.: 2 AF XY: 0.00147 AC XY: 677 AN XY: 462086

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

African (AFR) AF: 0.00211 AC: 45 AN: 21300

American (AMR) AF: 0.00727 AC: 66 AN: 9082

Ashkenazi Jewish (ASJ) AF: 0.00253 AC: 33 AN: 13068

East Asian (EAS) AF: 0.0151 AC: 303 AN: 20104

South Asian (SAS) AF: 0.00817 AC: 234 AN: 28652

European-Finnish (FIN) AF: 0.00238 AC: 49 AN: 20592

Middle Eastern (MID) AF: 0.00112 AC: 3 AN: 2682

European-Non Finnish (NFE) AF: 0.000617 AC: 503 AN: 815600

Other (OTH) AF: 0.00181 AC: 72 AN: 39748

⚠️ 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: 0.000253 AC: 38 AN: 149990 Hom.: 1 Cov.: 0 AF XY: 0.000355 AC XY: 26 AN XY: 73200

African (AFR) AF: 0.000122 AC: 5 AN: 41016

American (AMR) AF: 0.0000663 AC: 1 AN: 15080

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3444

East Asian (EAS) AF: 0.000584 AC: 3 AN: 5134

South Asian (SAS) AF: 0.00568 AC: 27 AN: 4752

European-Finnish (FIN) AF: 0.0000998 AC: 1 AN: 10016

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000149 AC: 1 AN: 67270

Other (OTH) AF: 0.00 AC: 0 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		-0.83

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;