10-49610915-G-C

Variant names:

• chr10-49610915-G-C
• NM_003055.3:c.175G>C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_003055.3(SLC18A3):​c.175G>C​(p.Asp59His) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 34)
• Consequence: SLC18A3 NM_003055.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.36

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC18A3	NM_003055.3	c.175G>C	p.Asp59His	missense_variant	Exon 1 of 1	ENST00000374115.5	NP_003046.2
CHAT	NM_020984.4	c.-69+1716G>C		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.175G>C	p.Asp59His	missense_variant	Exon 1 of 1	6	NM_003055.3	ENSP00000363229.3
CHAT	ENST00000339797.5	c.-69+1716G>C		intron_variant	Intron 1 of 14	1		ENSP00000343486.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 80

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Uncertain	0.012	T
BayesDel_noAF	Benign	-0.22
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.64	D
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.83	T
M_CAP	Uncertain	0.13	D
MetaRNN	Uncertain	0.62	D
MetaSVM	Uncertain	0.17	D
MutationAssessor	Uncertain	2.0	M
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-3.9	D
REVEL	Uncertain	0.57
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.020	D
Polyphen		0.90	P
Vest4		0.41
MutPred		0.66		Gain of disorder (P = 0.109);
MVP		0.79
ClinPred		0.90	D
GERP RS		1.9
Varity_R		0.24
gMVP		0.74

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr10-50818961;