8-20180955-T-G

Position:

• chr8-20180955-T-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_003053.4(SLC18A1):​c.10A>C​(p.Thr4Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.342 in 1,575,322 control chromosomes in the GnomAD database, including 94,988 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict 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 0.29 (7075 hom., cov: 32)
  • Exomes 𝑓: 0.35 (87913 hom.)
• Consequence: SLC18A1 NM_003053.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.759

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=0.0016539693).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.36 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC18A1	NM_003053.4	c.10A>C	p.Thr4Pro	missense_variant	2/16	ENST00000276373.10	NP_003044.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC18A1	ENST00000276373.10	c.10A>C	p.Thr4Pro	missense_variant	2/16	1	NM_003053.4	ENSP00000276373.5

Frequencies

GnomAD3 genomes AF: 0.289 AC: 43968 AN: 151914 Hom.: 7067 Cov.: 32

Gnomad AFR AF: 0.150

Gnomad AMI AF: 0.386

Gnomad AMR AF: 0.290

Gnomad ASJ AF: 0.390

Gnomad EAS AF: 0.257

Gnomad SAS AF: 0.290

Gnomad FIN AF: 0.321

Gnomad MID AF: 0.358

Gnomad NFE AF: 0.364

Gnomad OTH AF: 0.313

GnomAD3 exomes AF: 0.320 AC: 60510 AN: 189278 Hom.: 9829 AF XY: 0.322 AC XY: 32523 AN XY: 100890

Gnomad AFR exome AF: 0.148

Gnomad AMR exome AF: 0.266

Gnomad ASJ exome AF: 0.394

Gnomad EAS exome AF: 0.238

Gnomad SAS exome AF: 0.302

Gnomad FIN exome AF: 0.321

Gnomad NFE exome AF: 0.369

Gnomad OTH exome AF: 0.340

GnomAD4 exome AF: 0.348 AC: 495373 AN: 1423290 Hom.: 87913 Cov.: 35 AF XY: 0.347 AC XY: 244852 AN XY: 704630

Gnomad4 AFR exome AF: 0.138

Gnomad4 AMR exome AF: 0.266

Gnomad4 ASJ exome AF: 0.393

Gnomad4 EAS exome AF: 0.299

Gnomad4 SAS exome AF: 0.298

Gnomad4 FIN exome AF: 0.319

Gnomad4 NFE exome AF: 0.363

Gnomad4 OTH exome AF: 0.336

GnomAD4 genome AF: 0.289 AC: 44000 AN: 152032 Hom.: 7075 Cov.: 32 AF XY: 0.288 AC XY: 21398 AN XY: 74292

Gnomad4 AFR AF: 0.150

Gnomad4 AMR AF: 0.290

Gnomad4 ASJ AF: 0.390

Gnomad4 EAS AF: 0.257

Gnomad4 SAS AF: 0.291

Gnomad4 FIN AF: 0.321

Gnomad4 NFE AF: 0.364

Gnomad4 OTH AF: 0.317

Alfa AF: 0.339 Hom.: 10032

Bravo AF: 0.284

TwinsUK AF: 0.368 AC: 1365

ALSPAC AF: 0.368 AC: 1418

ESP6500AA AF: 0.156 AC: 686

ESP6500EA AF: 0.359 AC: 3086

ExAC AF: 0.279 AC: 32515

Asia WGS AF: 0.309 AC: 1077 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.74	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	7.3
DANN	Benign	0.89
DEOGEN2	Benign	0.062	.;T;T;.;.;.;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.53	.;.;T;T;T;.;T
MetaRNN	Benign	0.0017	T;T;T;T;T;T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	1.4	L;L;L;L;L;L;.
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.96	N;N;N;N;N;N;N
REVEL	Benign	0.025
Sift	Benign	0.23	T;T;T;T;T;T;T
Sift4G	Benign	0.21	T;T;T;D;T;D;T
Polyphen		0.0	.;B;B;.;.;.;.
Vest4		0.054
MPC		0.0019
ClinPred		0.0068	T
GERP RS		0.56
Varity_R		0.17
gMVP		0.55

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

Publications

LitVar

Other links and lift over

dbSNP: rs2270641; hg19: chr8-20038466; COSMIC: COSV52346450;