chr15-78596440-ATTT-A

Variant names:

• chr15-78596440-ATTT-A
• rs71148543
• NM_000743.5:c.*161_*163delAAA

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_000743.5(CHRNA3):​c.*161_*163delAAA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000102 in 976,362 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 0)
  • Exomes 𝑓: 0.0000010 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CHRNA3 NM_000743.5 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.830
• Publications: 0 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHRNA3	NM_000743.5	c.*161_*163delAAA		3_prime_UTR_variant	Exon 6 of 6	ENST00000326828.6	NP_000734.2
CHRNA3	XM_006720382.4	c.*161_*163delAAA		3_prime_UTR_variant	Exon 6 of 6		XP_006720445.1
CHRNA3	NM_001166694.2	c.1390-3252_1390-3250delAAA		intron_variant	Intron 5 of 5		NP_001160166.1
CHRNA3	NR_046313.2	n.1784+97_1784+99delAAA		intron_variant	Intron 6 of 7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHRNA3	ENST00000326828.6	c.*161_*163delAAA		3_prime_UTR_variant	Exon 6 of 6	1	NM_000743.5	ENSP00000315602.5
CHRNA3	ENST00000348639.7	c.1390-3252_1390-3250delAAA		intron_variant	Intron 5 of 5	1		ENSP00000267951.4
CHRNA3	ENST00000559002.5	n.193+97_193+99delAAA		intron_variant	Intron 1 of 1	1
CHRNA3	ENST00000559658.5	n.*64+97_*64+99delAAA		intron_variant	Intron 6 of 7	2		ENSP00000452896.1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 149896 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000102 AC: 1 AN: 976362 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 464782

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

African (AFR) AF: 0.00 AC: 0 AN: 21604

American (AMR) AF: 0.00 AC: 0 AN: 9254

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13148

East Asian (EAS) AF: 0.0000479 AC: 1 AN: 20882

South Asian (SAS) AF: 0.00 AC: 0 AN: 28916

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 20758

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2700

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 819072

Other (OTH) AF: 0.00 AC: 0 AN: 40028

⚠️ 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 Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 149896 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 73090

African (AFR) AF: 0.00 AC: 0 AN: 40906

American (AMR) AF: 0.00 AC: 0 AN: 15064

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5146

South Asian (SAS) AF: 0.00 AC: 0 AN: 4758

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10018

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67282

Other (OTH) AF: 0.00 AC: 0 AN: 2058

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;