rs11101192

Positions:

• chr10-49646721-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_020549.5(CHAT):​c.1281+47G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0174 in 1,600,960 control chromosomes in the GnomAD database, including 2,189 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.029 (276 hom., cov: 33)
  • Exomes 𝑓: 0.016 (1913 hom.)
• Consequence: CHAT NM_020549.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.24

Genes affected

CHAT (HGNC:1912): (choline O-acetyltransferase) This gene encodes an enzyme which catalyzes the biosynthesis of the neurotransmitter acetylcholine. This gene product is a characteristic feature of cholinergic neurons, and changes in these neurons may explain some of the symptoms of Alzheimer's disease. Polymorphisms in this gene have been associated with Alzheimer's disease and mild cognitive impairment. Mutations in this gene are associated with congenital myasthenic syndrome associated with episodic apnea. Multiple transcript variants encoding different isoforms have been found for this gene, and some of these variants have been shown to encode more than one isoform. [provided by RefSeq, May 2010]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 10-49646721-G-A is Benign according to our data. Variant chr10-49646721-G-A is described in ClinVar as [Benign]. Clinvar id is 261329.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.225 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHAT	NM_020549.5	c.1281+47G>A		intron_variant		ENST00000337653.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHAT	ENST00000337653.7	c.1281+47G>A		intron_variant		1	NM_020549.5	P2

Frequencies

GnomAD3 genomes AF: 0.0286 AC: 4357 AN: 152202 Hom.: 276 Cov.: 33

Gnomad AFR AF: 0.0297

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0987

Gnomad ASJ AF: 0.00518

Gnomad EAS AF: 0.236

Gnomad SAS AF: 0.0453

Gnomad FIN AF: 0.00358

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00101

Gnomad OTH AF: 0.0258

GnomAD3 exomes AF: 0.0550 AC: 12795 AN: 232518 Hom.: 1222 AF XY: 0.0481 AC XY: 6077 AN XY: 126226

Gnomad AFR exome AF: 0.0327

Gnomad AMR exome AF: 0.192

Gnomad ASJ exome AF: 0.00710

Gnomad EAS exome AF: 0.254

Gnomad SAS exome AF: 0.0445

Gnomad FIN exome AF: 0.00265

Gnomad NFE exome AF: 0.000824

Gnomad OTH exome AF: 0.0313

GnomAD4 exome AF: 0.0162 AC: 23482 AN: 1448642 Hom.: 1913 Cov.: 30 AF XY: 0.0161 AC XY: 11565 AN XY: 720548

Gnomad4 AFR exome AF: 0.0300

Gnomad4 AMR exome AF: 0.179

Gnomad4 ASJ exome AF: 0.00582

Gnomad4 EAS exome AF: 0.222

Gnomad4 SAS exome AF: 0.0410

Gnomad4 FIN exome AF: 0.00242

Gnomad4 NFE exome AF: 0.000769

Gnomad4 OTH exome AF: 0.0231

GnomAD4 genome AF: 0.0287 AC: 4364 AN: 152318 Hom.: 276 Cov.: 33 AF XY: 0.0306 AC XY: 2276 AN XY: 74480

Gnomad4 AFR AF: 0.0299

Gnomad4 AMR AF: 0.0988

Gnomad4 ASJ AF: 0.00518

Gnomad4 EAS AF: 0.236

Gnomad4 SAS AF: 0.0452

Gnomad4 FIN AF: 0.00358

Gnomad4 NFE AF: 0.00101

Gnomad4 OTH AF: 0.0250

Alfa AF: 0.0110 Hom.: 16

Bravo AF: 0.0396

Asia WGS AF: 0.130 AC: 452 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 08, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.3
DANN	Benign	0.46

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: rs11101192; hg19: chr10-50854767; COSMIC: COSV60335717;