8-20148043-G-C

Variant summary

Our verdict is Benign. Variant got -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. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• 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

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

Verdict is Benign. Variant got -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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC18A1	NM_003053.4	c.1174C>G	p.Leu392Val	missense_variant	13/16	ENST00000276373.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC18A1	ENST00000276373.10	c.1174C>G	p.Leu392Val	missense_variant	13/16	1	NM_003053.4	P1

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

GnomAD3 exomes AF: 0.0693 AC: 17397 AN: 251174 Hom.: 790 AF XY: 0.0686 AC XY: 9310 AN XY: 135744

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 SAS exome AF: 0.0143

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

Gnomad4 AFR exome AF: 0.0176

Gnomad4 AMR exome AF: 0.0388

Gnomad4 ASJ exome AF: 0.0711

Gnomad4 EAS exome AF: 0.0449

Gnomad4 SAS exome AF: 0.0155

Gnomad4 FIN exome AF: 0.0888

Gnomad4 NFE exome AF: 0.105

Gnomad4 OTH exome AF: 0.0832

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

Gnomad4 AFR AF: 0.0211

Gnomad4 AMR AF: 0.0535

Gnomad4 ASJ AF: 0.0769

Gnomad4 EAS AF: 0.0547

Gnomad4 SAS AF: 0.0164

Gnomad4 FIN AF: 0.0773

Gnomad4 NFE AF: 0.0973

Gnomad4 OTH AF: 0.0714

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 v4.3

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
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	0.99	D
MetaRNN	Benign	0.0036	T;T;T;T;T;T
MetaSVM	Benign	-0.53	T
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Uncertain	0.51	T
PROVEAN	Uncertain	-2.8	D;D;D;D;D;D
REVEL	Uncertain	0.45
Sift	Pathogenic	0.0	D;D;D;T;D;T
Sift4G	Uncertain	0.035	D;T;T;T;D;T
Polyphen		1.0	.;D;D;.;.;.
Vest4		0.48
MPC		0.0065
ClinPred		0.014	T
GERP RS		4.9
Varity_R		0.68
gMVP		0.86

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

Publications

LitVar

Other links and lift over

dbSNP: rs17092104; hg19: chr8-20005554; COSMIC: COSV52348085;