chr10-49610781-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBP6

The NM_003055.3(SLC18A3):c.41C>T(p.Ala14Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000739 in 1,570,614 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A14D) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 34)

Exomes 𝑓: 0.000070 ( 1 hom. )

Consequence

SLC18A3
NM_003055.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 4.16

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: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), ClinGen
presynaptic congenital myasthenic syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

CHAT links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0050925612).

BP6

Variant 10-49610781-C-T is Benign according to our data. Variant chr10-49610781-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1582049.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003055.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC18A3	NM_003055.3	MANE Select	c.41C>T	p.Ala14Val	missense	Exon 1 of 1	NP_003046.2	Q16572
	CHAT	NM_020984.4		c.-69+1582C>T		intron	N/A	NP_066264.4	P28329-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC18A3	ENST00000374115.5	TSL:6 MANE Select	c.41C>T	p.Ala14Val	missense	Exon 1 of 1	ENSP00000363229.3	Q16572
	CHAT	ENST00000339797.5	TSL:1	c.-69+1582C>T		intron	N/A	ENSP00000343486.1	P28329-3

Frequencies

GnomAD3 genomes

AF:

0.000112

AC:

AN:

152254

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00328

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000380

AC:

AN:

181570

AF XY:

0.000406

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00482

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000128

Gnomad OTH exome

AF:

0.000425

GnomAD4 exome

AF:

0.0000698

AC:

AN:

1418242

Hom.:

Cov.:

AF XY:

0.0000669

AC XY:

AN XY:

702262

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32350

American (AMR)

AF:

0.00

AC:

AN:

36340

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24448

East Asian (EAS)

AF:

0.00238

AC:

AN:

38198

South Asian (SAS)

AF:

0.00

AC:

AN:

80744

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50052

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5622

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1091810

Other (OTH)

AF:

0.000136

AC:

AN:

58678

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.511

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000112

AC:

AN:

152372

Hom.:

Cov.:

AF XY:

0.000174

AC XY:

AN XY:

74506

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41600

American (AMR)

AF:

0.00

AC:

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00329

AC:

AN:

5174

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68034

Other (OTH)

AF:

0.00

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.522

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000996

Hom.:

Bravo

AF:

0.000193

ExAC

AF:

0.000346

AC:

Asia WGS

AF:

0.000867

AC:

AN:

3476

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Congenital myasthenic syndrome 21 (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.093

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.55

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.13

Eigen

Benign

-0.63

Eigen_PC

Benign

-0.47

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.75

MetaRNN

Benign

0.0051

MetaSVM

Benign

-0.99

MutationAssessor

Benign

1.2

PhyloP100

4.2

PrimateAI

Pathogenic

0.81

PROVEAN

Benign

1.0

REVEL

Benign

0.054

Sift

Benign

0.96

Sift4G

Benign

0.43

Polyphen

0.036

Vest4

0.17

MVP

0.15

ClinPred

0.038

GERP RS

4.1

PromoterAI

-0.039

Neutral

(source)

Varity_R

0.049

gMVP

0.52

Mutation Taster

=61/39

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over