rs61731734

Positions:

• chr10-49619775-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_020549.5(CHAT):​c.438C>T​(p.Tyr146=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00329 in 1,614,028 control chromosomes in the GnomAD database, including 24 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0020 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0034 (21 hom.)
• Consequence: CHAT NM_020549.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.81

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant 10-49619775-C-T is Benign according to our data. Variant chr10-49619775-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 261336.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.81 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00205 (312/152340) while in subpopulation NFE AF= 0.00288 (196/68032). AF 95% confidence interval is 0.00255. There are 3 homozygotes in gnomad4. There are 141 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHAT	NM_020549.5	c.438C>T	p.Tyr146=	synonymous_variant	3/15	ENST00000337653.7	NP_065574.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHAT	ENST00000337653.7	c.438C>T	p.Tyr146=	synonymous_variant	3/15	1	NM_020549.5	ENSP00000337103	P2

Frequencies

GnomAD3 genomes AF: 0.00206 AC: 314 AN: 152222 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.000555

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00118

Gnomad ASJ AF: 0.0158

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00104

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00288

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00243 AC: 609 AN: 251080 Hom.: 1 AF XY: 0.00239 AC XY: 325 AN XY: 135772

Gnomad AFR exome AF: 0.000616

Gnomad AMR exome AF: 0.00130

Gnomad ASJ exome AF: 0.0133

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000490

Gnomad FIN exome AF: 0.00116

Gnomad NFE exome AF: 0.00313

Gnomad OTH exome AF: 0.00408

GnomAD4 exome AF: 0.00341 AC: 4991 AN: 1461688 Hom.: 21 Cov.: 32 AF XY: 0.00325 AC XY: 2365 AN XY: 727160

Gnomad4 AFR exome AF: 0.000568

Gnomad4 AMR exome AF: 0.00145

Gnomad4 ASJ exome AF: 0.0137

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000359

Gnomad4 FIN exome AF: 0.00127

Gnomad4 NFE exome AF: 0.00376

Gnomad4 OTH exome AF: 0.00445

GnomAD4 genome AF: 0.00205 AC: 312 AN: 152340 Hom.: 3 Cov.: 32 AF XY: 0.00189 AC XY: 141 AN XY: 74494

Gnomad4 AFR AF: 0.000553

Gnomad4 AMR AF: 0.00118

Gnomad4 ASJ AF: 0.0158

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00104

Gnomad4 NFE AF: 0.00288

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00348 Hom.: 0

Bravo AF: 0.00208

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00403

EpiControl AF: 0.00356

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 02, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 18, 2019	- -

not provided Benign:2

Likely benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 22, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	CHAT: BP4, BP7 -

CHAT-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 10, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Familial infantile myasthenia Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	5.3
DANN	Benign	0.60

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs61731734; hg19: chr10-50827821;