15-32030404-G-A

Position:

• chr15-32030404-G-A

Variant summary

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

The XM_047433397.1(LOC124903441):​c.41-16C>T variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00369 in 333,836 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0072 (14 hom., cov: 19)
  • Exomes 𝑓: 0.0011 (3 hom.)
• Consequence: LOC124903441 XM_047433397.1 splice_polypyrimidine_tract, intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.28

Genes affected

LOC124903441 (HGNC:):

CHRNA7 (HGNC:1960): (cholinergic receptor nicotinic alpha 7 subunit) The nicotinic acetylcholine receptors (nAChRs) are members of a superfamily of ligand-gated ion channels that mediate fast signal transmission at synapses. The nAChRs are thought to be hetero-pentamers composed of homologous subunits. The proposed structure for each subunit is a conserved N-terminal extracellular domain followed by three conserved transmembrane domains, a variable cytoplasmic loop, a fourth conserved transmembrane domain, and a short C-terminal extracellular region. The protein encoded by this gene forms a homo-oligomeric channel, displays marked permeability to calcium ions and is a major component of brain nicotinic receptors that are blocked by, and highly sensitive to, alpha-bungarotoxin. Once this receptor binds acetylcholine, it undergoes an extensive change in conformation that affects all subunits and leads to opening of an ion-conducting channel across the plasma membrane. This gene is located in a region identified as a major susceptibility locus for juvenile myoclonic epilepsy and a chromosomal location involved in the genetic transmission of schizophrenia. An evolutionarily recent partial duplication event in this region results in a hybrid containing sequence from this gene and a novel FAM7A gene. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2012]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 15-32030404-G-A is Benign according to our data. Variant chr15-32030404-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 1198672.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00717 (1015/141500) while in subpopulation AFR AF= 0.0248 (942/37938). AF 95% confidence interval is 0.0235. There are 14 homozygotes in gnomad4. There are 471 alleles in male gnomad4 subpopulation. Median coverage is 19. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 14 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LOC124903441	XM_047433397.1	c.41-16C>T		splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHRNA7	ENST00000635884.1	c.-132+430G>A		intron_variant		5
CHRNA7	ENST00000635978.1	c.-42-70899G>A		intron_variant		5
CHRNA7	ENST00000636603.1	c.-131-494G>A		intron_variant		5

Frequencies

GnomAD3 genomes AF: 0.00716 AC: 1012 AN: 141412 Hom.: 14 Cov.: 19

Gnomad AFR AF: 0.0248

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00164

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00233

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000467

Gnomad OTH AF: 0.00468

GnomAD4 exome AF: 0.00112 AC: 216 AN: 192336 Hom.: 3 AF XY: 0.00103 AC XY: 101 AN XY: 97632

Gnomad4 AFR exome AF: 0.0229

Gnomad4 AMR exome AF: 0.00297

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00266

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000390

Gnomad4 OTH exome AF: 0.00305

GnomAD4 genome AF: 0.00717 AC: 1015 AN: 141500 Hom.: 14 Cov.: 19 AF XY: 0.00684 AC XY: 471 AN XY: 68868

Gnomad4 AFR AF: 0.0248

Gnomad4 AMR AF: 0.00164

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00233

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000467

Gnomad4 OTH AF: 0.00464

Alfa AF: 0.000484 Hom.: 0

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

GeneDx

Dec 05, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	13
DANN	Benign	0.96

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs553179500; hg19: chr15-32322607;