8-20147283-C-T

Position:

• chr8-20147283-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_003053.4(SLC18A1):​c.1439G>A​(p.Ser480Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SLC18A1 NM_003053.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.372

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06418145).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC18A1	NM_003053.4	c.1439G>A	p.Ser480Asn	missense_variant	15/16	ENST00000276373.10	NP_003044.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC18A1	ENST00000276373.10	c.1439G>A	p.Ser480Asn	missense_variant	15/16	1	NM_003053.4	ENSP00000276373.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 14, 2023

The c.1439G>A (p.S480N) alteration is located in exon 15 (coding exon 14) of the SLC18A1 gene. This alteration results from a G to A substitution at nucleotide position 1439, causing the serine (S) at amino acid position 480 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	12
DANN	Benign	0.23
DEOGEN2	Benign	0.044	.;T;T;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.97
FATHMM_MKL	Benign	0.32	N
LIST_S2	Benign	0.74	.;.;T;T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.064	T;T;T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.10	.;N;N;.
PrimateAI	Benign	0.30	T
PROVEAN	Benign	0.91	N;N;N;N
REVEL	Benign	0.12
Sift	Benign	1.0	T;T;T;T
Sift4G	Benign	1.0	T;T;T;T
Polyphen		0.0020	.;B;B;.
Vest4		0.32
MutPred		0.24		.;Gain of catalytic residue at S480 (P = 0.0412);Gain of catalytic residue at S480 (P = 0.0412);.;
MVP		0.17
MPC		0.0023
ClinPred		0.036	T
GERP RS		0.13
Varity_R		0.032
gMVP		0.16

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: rs2071424570; hg19: chr8-20004794; COSMIC: COSV99368459; COSMIC: COSV99368459;