10-49610850-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_003055.3(SLC18A3):c.110T>C(p.Val37Ala) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 34)
• Consequence: SLC18A3 NM_003055.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.70

Genes affected

SLC18A3 (HGNC:10936): (solute carrier family 18 member A3) This gene is a member of the vesicular amine transporter family. The encoded transmembrane protein transports acetylcholine into secretory vesicles for release into the extracellular space. Acetylcholine transport utilizes a proton gradient established by a vacuolar ATPase. This gene is located within the first intron of the choline acetyltransferase gene. [provided by RefSeq, Jul 2008]

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC18A3	NM_003055.3	c.110T>C	p.Val37Ala	missense_variant	1/1	ENST00000374115.5
CHAT	NM_020984.4	c.-69+1651T>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC18A3	ENST00000374115.5	c.110T>C	p.Val37Ala	missense_variant	1/1		NM_003055.3	P1
CHAT	ENST00000339797.5	c.-69+1651T>C		intron_variant		1		A2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 79

GnomAD4 genome Cov.: 34

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Sep 21, 2021

This sequence change replaces valine with alanine at codon 37 of the SLC18A3 protein (p.Val37Ala). The valine residue is highly conserved and there is a small physicochemical difference between valine and alanine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with SLC18A3-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.038	T
BayesDel_noAF	Benign	-0.29
Cadd	Benign	23
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.60	D
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.72	T
M_CAP	Benign	0.073	D
MetaRNN	Uncertain	0.48	T
MetaSVM	Benign	-0.40	T
MutationAssessor	Uncertain	2.2	M
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.80	D
PROVEAN	Uncertain	-3.1	D
REVEL	Benign	0.18
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.035	D
Polyphen		0.97	D
Vest4		0.32
MutPred		0.35		Loss of sheet (P = 0.0357);
MVP		0.67
ClinPred		0.97	D
GERP RS		4.5
Varity_R		0.41
gMVP		0.45

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr10-50818896;