chr8-20148043-G-C

Variant names:

• chr8-20148043-G-C
• rs17092104
• NM_003053.4:c.1174C>G

Variant summary

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

The NM_003053.4(SLC18A1):​c.1174C>G​(p.Leu392Val) variant causes a missense change. The variant allele was found at a frequency of 0.0892 in 1,613,082 control chromosomes in the GnomAD database, including 7,302 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 0.066 (458 hom., cov: 32)
  • Exomes 𝑓: 0.092 (6844 hom.)
• Consequence: SLC18A1 NM_003053.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.61
• Publications: 29 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0036321878).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0954 is higher than 0.05.

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.1174C>G	p.Leu392Val	missense	Exon 13 of 16	NP_003044.1
	SLC18A1	NM_001135691.3		c.1174C>G	p.Leu392Val	missense	Exon 14 of 17	NP_001129163.1
	SLC18A1	NM_001438745.1		c.1090C>G	p.Leu364Val	missense	Exon 12 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.1174C>G	p.Leu392Val	missense	Exon 13 of 16	ENSP00000276373.5
	SLC18A1	ENST00000265808.11	TSL:1	c.1078C>G	p.Leu360Val	missense	Exon 13 of 16	ENSP00000265808.7
	SLC18A1	ENST00000440926.3	TSL:5	c.1174C>G	p.Leu392Val	missense	Exon 14 of 17	ENSP00000387549.1

Frequencies

GnomAD3 genomes AF: 0.0662 AC: 10070 AN: 152108 Hom.: 458 Cov.: 32

Gnomad AFR AF: 0.0211

Gnomad AMI AF: 0.141

Gnomad AMR AF: 0.0536

Gnomad ASJ AF: 0.0769

Gnomad EAS AF: 0.0550

Gnomad SAS AF: 0.0162

Gnomad FIN AF: 0.0773

Gnomad MID AF: 0.0759

Gnomad NFE AF: 0.0974

Gnomad OTH AF: 0.0722

GnomAD2 exomes AF: 0.0693 AC: 17397 AN: 251174 AF XY: 0.0686

Gnomad AFR exome AF: 0.0181

Gnomad AMR exome AF: 0.0376

Gnomad ASJ exome AF: 0.0694

Gnomad EAS exome AF: 0.0594

Gnomad FIN exome AF: 0.0871

Gnomad NFE exome AF: 0.0991

Gnomad OTH exome AF: 0.0714

GnomAD4 exome AF: 0.0916 AC: 133744 AN: 1460856 Hom.: 6844 Cov.: 32 AF XY: 0.0897 AC XY: 65164 AN XY: 726790

African (AFR) AF: 0.0176 AC: 588 AN: 33478

American (AMR) AF: 0.0388 AC: 1734 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.0711 AC: 1857 AN: 26132

East Asian (EAS) AF: 0.0449 AC: 1781 AN: 39694

South Asian (SAS) AF: 0.0155 AC: 1338 AN: 86240

European-Finnish (FIN) AF: 0.0888 AC: 4744 AN: 53410

Middle Eastern (MID) AF: 0.0758 AC: 436 AN: 5752

European-Non Finnish (NFE) AF: 0.105 AC: 116244 AN: 1111060

Other (OTH) AF: 0.0832 AC: 5022 AN: 60374

GnomAD4 genome AF: 0.0661 AC: 10064 AN: 152226 Hom.: 458 Cov.: 32 AF XY: 0.0638 AC XY: 4747 AN XY: 74426

African (AFR) AF: 0.0211 AC: 876 AN: 41536

American (AMR) AF: 0.0535 AC: 818 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0769 AC: 267 AN: 3470

East Asian (EAS) AF: 0.0547 AC: 283 AN: 5170

South Asian (SAS) AF: 0.0164 AC: 79 AN: 4822

European-Finnish (FIN) AF: 0.0773 AC: 820 AN: 10606

Middle Eastern (MID) AF: 0.0816 AC: 24 AN: 294

European-Non Finnish (NFE) AF: 0.0973 AC: 6618 AN: 68004

Other (OTH) AF: 0.0714 AC: 151 AN: 2114

Alfa AF: 0.0919 Hom.: 505

Bravo AF: 0.0640

TwinsUK AF: 0.102 AC: 377

ALSPAC AF: 0.105 AC: 404

ESP6500AA AF: 0.0263 AC: 116

ESP6500EA AF: 0.102 AC: 875

ExAC AF: 0.0694 AC: 8424

Asia WGS AF: 0.0320 AC: 110 AN: 3478

EpiCase AF: 0.100

EpiControl AF: 0.0972

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Uncertain	0.010
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.44	T
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D
MetaRNN	Benign	0.0036	T
MetaSVM	Benign	-0.53	T
MutationAssessor	Uncertain	2.9	M
PhyloP100		6.6
PrimateAI	Uncertain	0.51	T
PROVEAN	Uncertain	-2.8	D
REVEL	Uncertain	0.45
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.035	D
Polyphen		1.0	D
Vest4		0.48
MPC		0.0065
ClinPred		0.014	T
GERP RS		4.9
Varity_R		0.68
gMVP		0.86
Mutation Taster		=79/21	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs17092104; hg19: chr8-20005554; COSMIC: COSV52348085;