chr8-20179191-C-G

Variant names:

• chr8-20179191-C-G
• rs17215808
• NM_003053.4:c.418G>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_003053.4(SLC18A1):​c.418G>C​(p.Gly140Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: SLC18A1 NM_003053.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.23
• Publications: 0 publications found

Genes affected

SLC18A1 (HGNC:10934): (solute carrier family 18 member A1) The vesicular monoamine transporter acts to accumulate cytosolic monoamines into vesicles, using the proton gradient maintained across the vesicular membrane. Its proper function is essential to the correct activity of the monoaminergic systems that have been implicated in several human neuropsychiatric disorders. The transporter is a site of action of important drugs, including reserpine and tetrabenazine (Peter et al., 1993 [PubMed 7905859]). See also SLC18A2 (MIM 193001).[supplied by OMIM, Mar 2008]

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.838

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003053.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC18A1	NM_003053.4	MANE Select	c.418G>C	p.Gly140Arg	missense	Exon 3 of 16	NP_003044.1
	SLC18A1	NM_001135691.3		c.418G>C	p.Gly140Arg	missense	Exon 4 of 17	NP_001129163.1
	SLC18A1	NM_001438745.1		c.418G>C	p.Gly140Arg	missense	Exon 3 of 15	NP_001425674.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC18A1	ENST00000276373.10	TSL:1 MANE Select	c.418G>C	p.Gly140Arg	missense	Exon 3 of 16	ENSP00000276373.5
	SLC18A1	ENST00000265808.11	TSL:1	c.418G>C	p.Gly140Arg	missense	Exon 4 of 16	ENSP00000265808.7
	SLC18A1	ENST00000440926.3	TSL:5	c.418G>C	p.Gly140Arg	missense	Exon 4 of 17	ENSP00000387549.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.76
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.69	D
Eigen	Pathogenic	0.75
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.97	D
M_CAP	Uncertain	0.092	D
MetaRNN	Pathogenic	0.84	D
MetaSVM	Pathogenic	0.86	D
MutationAssessor	Pathogenic	3.9	H
PhyloP100		7.2
PrimateAI	Uncertain	0.61	T
PROVEAN	Pathogenic	-7.7	D
REVEL	Uncertain	0.54
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.98
MutPred		0.35		Gain of methylation at G140 (P = 0.0309)
MVP		0.72
MPC		0.0056
ClinPred		1.0	D
GERP RS		6.0
Varity_R		0.88
gMVP		0.98
Mutation Taster		=4/96	disease causing

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: rs17215808; hg19: chr8-20036702;