10-49610549-C-T

Variant names:

• chr10-49610549-C-T
• rs3750752
• NM_003055.3:c.-192C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_003055.3(SLC18A3):​c.-192C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0618 in 538,832 control chromosomes in the GnomAD database, including 2,366 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.069 (768 hom., cov: 33)
  • Exomes 𝑓: 0.059 (1598 hom.)
• Consequence: SLC18A3 NM_003055.3 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.468
• Publications: 7 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.226 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC18A3	NM_003055.3	c.-192C>T		5_prime_UTR_variant	Exon 1 of 1	ENST00000374115.5	NP_003046.2
CHAT	NM_020984.4	c.-69+1350C>T		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.-192C>T		5_prime_UTR_variant	Exon 1 of 1	6	NM_003055.3	ENSP00000363229.3
CHAT	ENST00000339797.5	c.-69+1350C>T		intron_variant	Intron 1 of 14	1		ENSP00000343486.1

Frequencies

GnomAD3 genomes AF: 0.0685 AC: 10429 AN: 152158 Hom.: 751 Cov.: 33

Gnomad AFR AF: 0.0611

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.232

Gnomad ASJ AF: 0.0377

Gnomad EAS AF: 0.224

Gnomad SAS AF: 0.0876

Gnomad FIN AF: 0.0357

Gnomad MID AF: 0.0223

Gnomad NFE AF: 0.0308

Gnomad OTH AF: 0.0769

GnomAD4 exome AF: 0.0591 AC: 22830 AN: 386562 Hom.: 1598 Cov.: 5 AF XY: 0.0591 AC XY: 11706 AN XY: 198178

African (AFR) AF: 0.0593 AC: 494 AN: 8330

American (AMR) AF: 0.291 AC: 2979 AN: 10232

Ashkenazi Jewish (ASJ) AF: 0.0414 AC: 481 AN: 11612

East Asian (EAS) AF: 0.232 AC: 5801 AN: 25002

South Asian (SAS) AF: 0.0847 AC: 1885 AN: 22268

European-Finnish (FIN) AF: 0.0399 AC: 1116 AN: 27974

Middle Eastern (MID) AF: 0.0525 AC: 95 AN: 1808

European-Non Finnish (NFE) AF: 0.0326 AC: 8353 AN: 256248

Other (OTH) AF: 0.0704 AC: 1626 AN: 23088

GnomAD4 genome AF: 0.0687 AC: 10464 AN: 152270 Hom.: 768 Cov.: 33 AF XY: 0.0734 AC XY: 5464 AN XY: 74444

African (AFR) AF: 0.0610 AC: 2535 AN: 41570

American (AMR) AF: 0.233 AC: 3562 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0377 AC: 131 AN: 3472

East Asian (EAS) AF: 0.224 AC: 1151 AN: 5136

South Asian (SAS) AF: 0.0871 AC: 421 AN: 4834

European-Finnish (FIN) AF: 0.0357 AC: 379 AN: 10620

Middle Eastern (MID) AF: 0.0240 AC: 7 AN: 292

European-Non Finnish (NFE) AF: 0.0308 AC: 2093 AN: 68014

Other (OTH) AF: 0.0846 AC: 179 AN: 2116

Alfa AF: 0.0497 Hom.: 712

Bravo AF: 0.0883

Asia WGS AF: 0.179 AC: 620 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	9.4
DANN	Benign	0.71
PhyloP100		0.47
PromoterAI		-0.026	Neutral
Mutation Taster		=295/5	polymorphism (auto)

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: rs3750752; hg19: chr10-50818595;