rs1838268773

Variant names:

• chr10-49610751-C-A
• rs1838268773
• NM_003055.3:c.11C>A

Your query was ambiguous. Multiple possible variants found:

• chr10-49610751-C-A
• chr10-49610751-C-G
• chr10-49610751-C-T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_003055.3(SLC18A3):​c.11C>A​(p.Ala4Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000728 in 1,372,758 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 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. A4G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 7.3e-7 (0 hom.)
• Consequence: SLC18A3 NM_003055.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0710
• Publications: 0 publications found

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]

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

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.03957966).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC18A3	NM_003055.3	c.11C>A	p.Ala4Glu	missense_variant	Exon 1 of 1	ENST00000374115.5	NP_003046.2
CHAT	NM_020984.4	c.-69+1552C>A		intron_variant	Intron 1 of 14		NP_066264.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC18A3	ENST00000374115.5	c.11C>A	p.Ala4Glu	missense_variant	Exon 1 of 1	6	NM_003055.3	ENSP00000363229.3
CHAT	ENST00000339797.5	c.-69+1552C>A		intron_variant	Intron 1 of 14	1		ENSP00000343486.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 7.28e-7 AC: 1 AN: 1372758 Hom.: 0 Cov.: 79 AF XY: 0.00000148 AC XY: 1 AN XY: 675698

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 31054

American (AMR) AF: 0.00 AC: 0 AN: 28596

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21952

East Asian (EAS) AF: 0.00 AC: 0 AN: 37244

South Asian (SAS) AF: 0.0000137 AC: 1 AN: 72972

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47204

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5398

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1071480

Other (OTH) AF: 0.00 AC: 0 AN: 56858

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.78
CADD	Benign	0.15
DANN	Benign	0.91
DEOGEN2	Benign	0.12	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.058	N
LIST_S2	Benign	0.27	T
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.040	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	-0.26	N
PhyloP100		-0.071
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	0.20	N
REVEL	Benign	0.054
Sift	Benign	0.68	T
Sift4G	Benign	0.83	T
Polyphen		0.0	B
Vest4		0.072
MutPred		0.065		Gain of solvent accessibility (P = 0.154);
MVP		0.25
ClinPred		0.030	T
GERP RS		-2.5
PromoterAI		-0.018	Neutral
Varity_R		0.052
gMVP		0.24
Mutation Taster		=92/8	polymorphism

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

Other links and lift over

dbSNP: rs1838268773; hg19: chr10-50818797;