rs3750752

Positions:

• chr10-49610549-C-T

Variant summary

Our verdict is Benign. Variant got -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

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 Benign. Variant got -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/exons	MANE	Protein	UniProt
SLC18A3	NM_003055.3	c.-192C>T		5_prime_UTR_variant	1/1	ENST00000374115.5	NP_003046.2
CHAT	NM_020984.4	c.-69+1350C>T		intron_variant			NP_066264.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC18A3	ENST00000374115.5	c.-192C>T		5_prime_UTR_variant	1/1	6	NM_003055.3	ENSP00000363229.3
CHAT	ENST00000339797.5	c.-69+1350C>T		intron_variant		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

Gnomad4 AFR exome AF: 0.0593

Gnomad4 AMR exome AF: 0.291

Gnomad4 ASJ exome AF: 0.0414

Gnomad4 EAS exome AF: 0.232

Gnomad4 SAS exome AF: 0.0847

Gnomad4 FIN exome AF: 0.0399

Gnomad4 NFE exome AF: 0.0326

Gnomad4 OTH exome AF: 0.0704

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

Gnomad4 AFR AF: 0.0610

Gnomad4 AMR AF: 0.233

Gnomad4 ASJ AF: 0.0377

Gnomad4 EAS AF: 0.224

Gnomad4 SAS AF: 0.0871

Gnomad4 FIN AF: 0.0357

Gnomad4 NFE AF: 0.0308

Gnomad4 OTH AF: 0.0846

Alfa AF: 0.0464 Hom.: 523

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

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: rs3750752; hg19: chr10-50818595;