NM_003053.4:c.293G>C

Variant names:

• chr8-20179316-C-G
• rs2270637
• NM_003053.4:c.293G>C

Variant summary

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

The NM_003053.4(SLC18A1):​c.293G>C​(p.Ser98Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.197 in 1,613,998 control chromosomes in the GnomAD database, including 32,335 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.21 (3378 hom., cov: 33)
  • Exomes 𝑓: 0.20 (28957 hom.)
• Consequence: SLC18A1 NM_003053.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.888
• Publications: 41 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=0.0053890646).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.229 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC18A1	NM_003053.4	MANE Select	c.293G>C	p.Ser98Thr	missense	Exon 3 of 16	NP_003044.1	P54219-1
	SLC18A1	NM_001135691.3		c.293G>C	p.Ser98Thr	missense	Exon 4 of 17	NP_001129163.1	P54219-1
	SLC18A1	NM_001438745.1		c.293G>C	p.Ser98Thr	missense	Exon 3 of 15	NP_001425674.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC18A1	ENST00000276373.10	TSL:1 MANE Select	c.293G>C	p.Ser98Thr	missense	Exon 3 of 16	ENSP00000276373.5	P54219-1
	SLC18A1	ENST00000265808.11	TSL:1	c.293G>C	p.Ser98Thr	missense	Exon 4 of 16	ENSP00000265808.7	P54219-3
	SLC18A1	ENST00000440926.3	TSL:5	c.293G>C	p.Ser98Thr	missense	Exon 4 of 17	ENSP00000387549.1	P54219-1

Frequencies

GnomAD3 genomes AF: 0.205 AC: 31233 AN: 152034 Hom.: 3377 Cov.: 33

Gnomad AFR AF: 0.233

Gnomad AMI AF: 0.174

Gnomad AMR AF: 0.166

Gnomad ASJ AF: 0.155

Gnomad EAS AF: 0.157

Gnomad SAS AF: 0.224

Gnomad FIN AF: 0.279

Gnomad MID AF: 0.130

Gnomad NFE AF: 0.192

Gnomad OTH AF: 0.190

GnomAD2 exomes AF: 0.195 AC: 49121 AN: 251384 AF XY: 0.196

Gnomad AFR exome AF: 0.229

Gnomad AMR exome AF: 0.166

Gnomad ASJ exome AF: 0.162

Gnomad EAS exome AF: 0.136

Gnomad FIN exome AF: 0.278

Gnomad NFE exome AF: 0.190

Gnomad OTH exome AF: 0.189

GnomAD4 exome AF: 0.196 AC: 287216 AN: 1461846 Hom.: 28957 Cov.: 58 AF XY: 0.196 AC XY: 142607 AN XY: 727224

African (AFR) AF: 0.235 AC: 7864 AN: 33478

American (AMR) AF: 0.165 AC: 7377 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.158 AC: 4125 AN: 26136

East Asian (EAS) AF: 0.198 AC: 7849 AN: 39698

South Asian (SAS) AF: 0.221 AC: 19060 AN: 86254

European-Finnish (FIN) AF: 0.274 AC: 14663 AN: 53420

Middle Eastern (MID) AF: 0.172 AC: 990 AN: 5762

European-Non Finnish (NFE) AF: 0.192 AC: 213802 AN: 1111986

Other (OTH) AF: 0.190 AC: 11486 AN: 60390

GnomAD4 genome AF: 0.205 AC: 31250 AN: 152152 Hom.: 3378 Cov.: 33 AF XY: 0.207 AC XY: 15373 AN XY: 74374

African (AFR) AF: 0.233 AC: 9660 AN: 41504

American (AMR) AF: 0.167 AC: 2548 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.155 AC: 538 AN: 3470

East Asian (EAS) AF: 0.157 AC: 807 AN: 5156

South Asian (SAS) AF: 0.224 AC: 1078 AN: 4818

European-Finnish (FIN) AF: 0.279 AC: 2945 AN: 10572

Middle Eastern (MID) AF: 0.126 AC: 37 AN: 294

European-Non Finnish (NFE) AF: 0.192 AC: 13080 AN: 68010

Other (OTH) AF: 0.188 AC: 398 AN: 2114

Alfa AF: 0.190 Hom.: 2151

Bravo AF: 0.194

TwinsUK AF: 0.188 AC: 697

ALSPAC AF: 0.181 AC: 697

ESP6500AA AF: 0.222 AC: 978

ESP6500EA AF: 0.191 AC: 1640

ExAC AF: 0.197 AC: 23951

Asia WGS AF: 0.192 AC: 670 AN: 3478

EpiCase AF: 0.182

EpiControl AF: 0.172

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.81	T
BayesDel_noAF	Benign	-0.79
CADD	Benign	0.10
DANN	Benign	0.29
DEOGEN2	Benign	0.043	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.60	T
MetaRNN	Benign	0.0054	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.13	N
PhyloP100		-0.89
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-0.41	N
REVEL	Benign	0.010
Sift	Benign	0.50	T
Sift4G	Benign	0.60	T
Polyphen		0.033	B
Vest4		0.12
MPC		0.0025
ClinPred		0.0020	T
GERP RS		-5.8
Varity_R		0.044
gMVP		0.49
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2270637; hg19: chr8-20036827; COSMIC: COSV52347806; COSMIC: COSV52347806;