rs1880676

chr10-49616071-G-A

Variant summary

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

The ENST00000395562.2(CHAT):c.19G>A(p.Asp7Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.237 in 1,612,640 control chromosomes in the GnomAD database, including 47,820 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/14 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.18 (3033 hom., cov: 34)
  • Exomes 𝑓: 0.24 (44787 hom.)
• Consequence: CHAT ENST00000395562.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.43

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 (MetaRNN=0.0045491755).
• BP6: Variant 10-49616071-G-A is Benign according to our data. Variant chr10-49616071-G-A is described in ClinVar as [Benign]. Clinvar id is 402536.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.26 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHAT	NM_020549.5	c.287-431G>A		intron_variant		ENST00000337653.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHAT	ENST00000337653.7	c.287-431G>A		intron_variant		1	NM_020549.5	P2

Frequencies

GnomAD3 genomes AF: 0.179 AC: 27293 AN: 152130 Hom.: 3036 Cov.: 34

Gnomad AFR AF: 0.0482

Gnomad AMI AF: 0.268

Gnomad AMR AF: 0.184

Gnomad ASJ AF: 0.234

Gnomad EAS AF: 0.159

Gnomad SAS AF: 0.273

Gnomad FIN AF: 0.181

Gnomad MID AF: 0.213

Gnomad NFE AF: 0.248

Gnomad OTH AF: 0.192

GnomAD3 exomes AF: 0.210 AC: 52261 AN: 248860 Hom.: 6115 AF XY: 0.220 AC XY: 29810 AN XY: 135228

Gnomad AFR exome AF: 0.0416

Gnomad AMR exome AF: 0.144

Gnomad ASJ exome AF: 0.244

Gnomad EAS exome AF: 0.147

Gnomad SAS exome AF: 0.276

Gnomad FIN exome AF: 0.180

Gnomad NFE exome AF: 0.247

Gnomad OTH exome AF: 0.230

GnomAD4 exome AF: 0.243 AC: 354404 AN: 1460392 Hom.: 44787 Cov.: 33 AF XY: 0.245 AC XY: 177869 AN XY: 726552

Gnomad4 AFR exome AF: 0.0393

Gnomad4 AMR exome AF: 0.149

Gnomad4 ASJ exome AF: 0.246

Gnomad4 EAS exome AF: 0.174

Gnomad4 SAS exome AF: 0.276

Gnomad4 FIN exome AF: 0.186

Gnomad4 NFE exome AF: 0.255

Gnomad4 OTH exome AF: 0.235

GnomAD4 genome AF: 0.179 AC: 27284 AN: 152248 Hom.: 3033 Cov.: 34 AF XY: 0.179 AC XY: 13325 AN XY: 74438

Gnomad4 AFR AF: 0.0481

Gnomad4 AMR AF: 0.184

Gnomad4 ASJ AF: 0.234

Gnomad4 EAS AF: 0.158

Gnomad4 SAS AF: 0.273

Gnomad4 FIN AF: 0.181

Gnomad4 NFE AF: 0.248

Gnomad4 OTH AF: 0.191

Alfa AF: 0.237 Hom.: 8758

Bravo AF: 0.170

TwinsUK AF: 0.257 AC: 953

ALSPAC AF: 0.272 AC: 1049

ESP6500AA AF: 0.0501 AC: 157

ESP6500EA AF: 0.248 AC: 1775

ExAC AF: 0.211 AC: 25417

Asia WGS AF: 0.191 AC: 663 AN: 3478

EpiCase AF: 0.261

EpiControl AF: 0.259

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 28, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: MAF -

Familial infantile myasthenia Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 19, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 19, 2018

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.42
Cadd	Benign	7.6
Dann	Uncertain	0.99
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.46
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.32	T
MetaRNN	Benign	0.0045	T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	P;P;P;P;P;P
PROVEAN	Benign	0.13	N
REVEL	Benign	0.17
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.81	T
Vest4		0.051
ClinPred		0.029	T
GERP RS		3.2

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: rs1880676; hg19: chr10-50824117; COSMIC: COSV60323720; COSMIC: COSV60323720;