chr10-49610779-G-C

Variant names:

• chr10-49610779-G-C
• rs755134161
• NM_003055.3:c.39G>C

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The NM_003055.3(SLC18A3):​c.39G>C​(p.Ala13Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000141 in 1,415,654 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. A13A) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 35)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SLC18A3 NM_003055.3 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.00
• 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: DEFINITIVE, STRONG Submitted by: ClinGen, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), PanelApp Australia
• presynaptic congenital myasthenic syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP7: Synonymous conserved (PhyloP=-1 with no splicing effect.

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.39G>C	p.Ala13Ala	synonymous	Exon 1 of 1	NP_003046.2	Q16572
	CHAT	NM_020984.4		c.-69+1580G>C		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.39G>C	p.Ala13Ala	synonymous	Exon 1 of 1	ENSP00000363229.3	Q16572
	CHAT	ENST00000339797.5	TSL:1	c.-69+1580G>C		intron	N/A	ENSP00000343486.1	P28329-3

Frequencies

GnomAD3 genomes Cov.: 35

GnomAD4 exome AF: 0.00000141 AC: 2 AN: 1415654 Hom.: 0 Cov.: 79 AF XY: 0.00000285 AC XY: 2 AN XY: 700818

African (AFR) AF: 0.00 AC: 0 AN: 32264

American (AMR) AF: 0.00 AC: 0 AN: 35788

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24290

East Asian (EAS) AF: 0.00 AC: 0 AN: 38130

South Asian (SAS) AF: 0.00 AC: 0 AN: 80446

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49904

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5602

European-Non Finnish (NFE) AF: 0.00000183 AC: 2 AN: 1090694

Other (OTH) AF: 0.00 AC: 0 AN: 58536

GnomAD4 genome Cov.: 35

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	4.4
DANN	Benign	0.80
PhyloP100		-1.0
PromoterAI		0.023	Neutral

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: rs755134161; hg19: chr10-50818825;