10-49610825-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_Strong BP6

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 2.06

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 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, Benign=1}.

Transcripts

RefSeq

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

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.00184 AC: 280 AN: 152246 Hom.: 1 Cov.: 35

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.: 0 AF XY: 0.000369 AC XY: 47 AN XY: 127532

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.: 1 Cov.: 80 AF XY: 0.000142 AC XY: 103 AN XY: 723060

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.: 1 Cov.: 35 AF XY: 0.00161 AC XY: 120 AN XY: 74508

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.: 0

Bravo AF: 0.00213

ESP6500AA AF: 0.00523 AC: 23

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000471 AC: 57

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:2

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

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	T
BayesDel_noAF	Benign	-0.44
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.67	D
Eigen	Benign	0.0077
Eigen_PC	Benign	0.023
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.046	D
MetaRNN	Benign	0.011	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	L
MutationTaster	Benign	1.0	D;N
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-2.9	D
REVEL	Benign	0.12
Sift	Uncertain	0.0020	D
Sift4G	Pathogenic	0.0010	D
Polyphen		0.99	D
Vest4		0.29
MVP		0.80
ClinPred		0.032	T
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

Other links and lift over

dbSNP: rs8187734; hg19: chr10-50818871;