NM_020549.5:c.1381G>C

Variant names:

• chr10-49648606-G-C
• rs4838544
• NM_020549.5:c.1381G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_020549.5(CHAT):​c.1381G>C​(p.Val461Leu) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V461A) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CHAT NM_020549.5 missense, splice_region
• Scores: Splicing: ADA: 0.2529
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.30
• Publications: 28 publications found

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]

CHAT Gene-Disease associations (from GenCC):

• congenital myasthenic syndrome 6

  Inheritance: AR Classification: STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• presynaptic congenital myasthenic syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17910424).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHAT	NM_020549.5	c.1381G>C	p.Val461Leu	missense_variant, splice_region_variant	Exon 9 of 15	ENST00000337653.7	NP_065574.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHAT	ENST00000337653.7	c.1381G>C	p.Val461Leu	missense_variant, splice_region_variant	Exon 9 of 15	1	NM_020549.5	ENSP00000337103.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Uncertain	0.037	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.19	.;.;.;T;.;.
Eigen	Benign	-0.64
Eigen_PC	Benign	-0.44
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.29	.;.;T;T;T;T
M_CAP	Benign	0.077	D
MetaRNN	Benign	0.18	T;T;T;T;T;T
MetaSVM	Benign	-0.58	T
MutationAssessor	Benign	-0.32	.;.;.;N;.;.
PhyloP100		5.3
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-0.050	N;N;N;N;N;.
REVEL	Benign	0.28
Sift	Benign	0.15	T;T;T;T;T;.
Sift4G	Benign	0.19	T;T;T;T;T;.
Polyphen		0.0080	.;.;.;B;.;.
Vest4		0.13
MutPred		0.61		.;.;.;Loss of MoRF binding (P = 0.086);.;.;
MVP		0.75
MPC		0.25
ClinPred		0.75	D
GERP RS		3.9
Varity_R		0.12
gMVP		0.47
Mutation Taster		=87/13	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.25
dbscSNV1_RF	Benign	0.51
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

Other links and lift over

dbSNP: rs4838544; hg19: chr10-50856652;