rs76014951

chr10-49648597-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_020549.5(CHAT):c.1372C>T(p.Leu458Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00511 in 1,611,882 control chromosomes in the GnomAD database, including 29 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0037 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0053 (26 hom.)
• Consequence: CHAT NM_020549.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 7.91

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=0.013102263).
• BP6: Variant 10-49648597-C-T is Benign according to our data. Variant chr10-49648597-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 199158.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-49648597-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00367 (559/152292) while in subpopulation NFE AF= 0.00523 (356/68028). AF 95% confidence interval is 0.00478. There are 3 homozygotes in gnomad4. There are 302 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHAT	NM_020549.5	c.1372C>T	p.Leu458Phe	missense_variant	9/15	ENST00000337653.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHAT	ENST00000337653.7	c.1372C>T	p.Leu458Phe	missense_variant	9/15	1	NM_020549.5	P2

Frequencies

GnomAD3 genomes AF: 0.00367 AC: 559 AN: 152174 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00113

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000981

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0130

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00523

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.00388 AC: 967 AN: 249232 Hom.: 5 AF XY: 0.00372 AC XY: 502 AN XY: 134800

Gnomad AFR exome AF: 0.000808

Gnomad AMR exome AF: 0.000958

Gnomad ASJ exome AF: 0.0000995

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000132

Gnomad FIN exome AF: 0.0150

Gnomad NFE exome AF: 0.00505

Gnomad OTH exome AF: 0.00477

GnomAD4 exome AF: 0.00527 AC: 7685 AN: 1459590 Hom.: 26 Cov.: 31 AF XY: 0.00504 AC XY: 3659 AN XY: 726158

Gnomad4 AFR exome AF: 0.000598

Gnomad4 AMR exome AF: 0.000917

Gnomad4 ASJ exome AF: 0.000115

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000139

Gnomad4 FIN exome AF: 0.0131

Gnomad4 NFE exome AF: 0.00594

Gnomad4 OTH exome AF: 0.00507

GnomAD4 genome AF: 0.00367 AC: 559 AN: 152292 Hom.: 3 Cov.: 32 AF XY: 0.00406 AC XY: 302 AN XY: 74462

Gnomad4 AFR AF: 0.00113

Gnomad4 AMR AF: 0.000980

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.0130

Gnomad4 NFE AF: 0.00523

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.00468 Hom.: 4

Bravo AF: 0.00271

TwinsUK AF: 0.00647 AC: 24

ALSPAC AF: 0.00467 AC: 18

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.00407 AC: 35

ExAC AF: 0.00365 AC: 443

EpiCase AF: 0.00442

EpiControl AF: 0.00541

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2023	CHAT: BS2 -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 23, 2014	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Familial infantile myasthenia Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Uncertain	0.074	D
BayesDel_noAF	Pathogenic	0.34
Cadd	Uncertain	25
Dann	Uncertain	1.0
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.95	D
MetaRNN	Benign	0.013	T;T;T;T;T;T
MetaSVM	Uncertain	0.57	D
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-2.2	N;N;N;N;N;.
REVEL	Pathogenic	0.83
Sift	Benign	0.070	T;T;T;T;T;.
Sift4G	Benign	0.12	T;T;T;T;T;.
Polyphen		1.0	.;.;.;D;.;.
Vest4		0.77
MVP		0.97
MPC		0.93
ClinPred		0.014	T
GERP RS		5.0
Varity_R		0.69
gMVP		0.67

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: rs76014951; hg19: chr10-50856643;