chr10-49610825-C-T

Position:

chr10-49610825-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_StrongBP6

The NM_003055.3(SLC18A3):c.85C>T(p.Arg29Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000338 in 1,606,874 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0018 ( 1 hom., cov: 35)

Exomes 𝑓: 0.00018 ( 1 hom. )

Consequence

SLC18A3
NM_003055.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:3

Conservation

PhyloP100: 2.06

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.011109948).

BP6

Variant 10-49610825-C-T is Benign according to our data. Variant chr10-49610825-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 732977.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC18A3	NM_003055.3 linkuse as main transcript	c.85C>T	p.Arg29Trp	missense_variant	1/1	ENST00000374115.5
CHAT	NM_020984.4 linkuse as main transcript	c.-69+1626C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC18A3	ENST00000374115.5 linkuse as main transcript	c.85C>T	p.Arg29Trp	missense_variant	1/1		NM_003055.3	P1
CHAT	ENST00000339797.5 linkuse as main transcript	c.-69+1626C>T		intron_variant		1		A2	P28329-3

Frequencies

GnomAD3 genomes

AF:

0.00184

AC:

280

AN:

152246

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00666

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000491

AC:

115

AN:

234340

Hom.:

AF XY:

0.000369

AC XY:

AN XY:

127532

show subpopulations

Gnomad AFR exome

AF:

0.00691

Gnomad AMR exome

AF:

0.000390

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000340

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000173

GnomAD4 exome

AF:

0.000181

AC:

263

AN:

1454510

Hom.:

Cov.:

AF XY:

0.000142

AC XY:

103

AN XY:

723060

show subpopulations

Gnomad4 AFR exome

AF:

0.00680

Gnomad4 AMR exome

AF:

0.000389

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000117

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000541

Gnomad4 OTH exome

AF:

0.000200

GnomAD4 genome

AF:

0.00184

AC:

280

AN:

152364

Hom.:

Cov.:

AF XY:

0.00161

AC XY:

120

AN XY:

74508

show subpopulations

Gnomad4 AFR

AF:

0.00664

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000723

Hom.:

Bravo

AF:

0.00213

ESP6500AA

AF:

0.00523

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000471

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2022	SLC18A3: BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -

Congenital myasthenic syndrome 21

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Jan 29, 2018

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

SLC18A3-related disorder

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 17, 2020

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

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.44

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.67

Eigen

Benign

0.0077

Eigen_PC

Benign

0.023

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.94

M_CAP

Benign

0.046

MetaRNN

Benign

0.011

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.8

MutationTaster

Benign

1.0

D;N

PrimateAI

Uncertain

0.53

PROVEAN

Uncertain

-2.9

REVEL

Benign

0.12

Sift

Uncertain

0.0020

Sift4G

Pathogenic

0.0010

Polyphen

0.99

Vest4

0.29

MVP

0.80

ClinPred

0.032

GERP RS

3.2

Varity_R

0.18

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over