Genetic Variant SLC18A3:p.Gly22Arg (chr10-49610804-G-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_003055.3(SLC18A3):c.64G>C(p.Gly22Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000000694 in 1,441,558 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G22S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 35)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

SLC18A3
NM_003055.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 6.36

Publications

0 publications found

Variant links:

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]

SLC18A3 links:

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

CHAT links:

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ACMG classification

Classification was made for transcript

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=0.18533707).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC18A3	NM_003055.3 link	c.64G>C	p.Gly22Arg	missense_variant	Exon 1 of 1	ENST00000374115.5	NP_003046.2	Q16572
CHAT	NM_020984.4 link	c.-69+1605G>C		intron_variant	Intron 1 of 14		NP_066264.4	P28329-3D3DX95

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC18A3	ENST00000374115.5 link	c.64G>C	p.Gly22Arg	missense_variant	Exon 1 of 1	6	NM_003055.3	ENSP00000363229.3		Q16572
CHAT	ENST00000339797.5 link	c.-69+1605G>C		intron_variant	Intron 1 of 14	1		ENSP00000343486.1		P28329-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.94e-7

AC:

AN:

1441558

Hom.:

Cov.:

AF XY:

0.00000140

AC XY:

AN XY:

715610

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33088

American (AMR)

AF:

0.00

AC:

AN:

41134

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25542

East Asian (EAS)

AF:

0.00

AC:

AN:

38846

South Asian (SAS)

AF:

0.00

AC:

AN:

83684

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51206

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5716

European-Non Finnish (NFE)

AF:

9.07e-7

AC:

AN:

1102794

Other (OTH)

AF:

0.00

AC:

AN:

59548

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.625

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.40

CADD

Benign

(source)

DANN

Benign

0.87

DEOGEN2

Benign

0.20

Eigen

Benign

-0.38

Eigen_PC

Benign

-0.20

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.73

M_CAP

Benign

0.022

MetaRNN

Benign

0.19

MetaSVM

Benign

-0.87

MutationAssessor

Uncertain

2.0

PhyloP100

6.4

PrimateAI

Pathogenic

0.82

PROVEAN

Benign

-1.3

REVEL

Benign

0.17

Sift

Benign

0.67

Sift4G

Benign

0.65

Polyphen

0.017

Vest4

0.43

MutPred

0.34

Gain of MoRF binding (P = 0.0071);

MVP

0.24

ClinPred

0.22

GERP RS

4.1

PromoterAI

-0.013

Neutral

(source)

Varity_R

0.21

gMVP

0.67

Mutation Taster

=60/40

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over