rs28914833

chr17-30210571-A-G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001045.6(SLC6A4):c.1393T>C(p.Phe465Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000225 in 1,613,894 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. F465F) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00013 (0 hom.)
• Consequence: SLC6A4 NM_001045.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 5.35

Genes affected

SLC6A4 (HGNC:11050): (solute carrier family 6 member 4) This gene encodes an integral membrane protein that transports the neurotransmitter serotonin from synaptic spaces into presynaptic neurons. The encoded protein terminates the action of serotonin and recycles it in a sodium-dependent manner. This protein is a target of psychomotor stimulants, such as amphetamines and cocaine, and is a member of the sodium:neurotransmitter symporter family. A repeat length polymorphism in the promoter of this gene has been shown to affect the rate of serotonin uptake. There have been conflicting results in the literature about the possible effect, if any, that this polymorphism may play in behavior and depression. [provided by RefSeq, May 2019]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0123232305).
• BP6: Variant 17-30210571-A-G is Benign according to our data. Variant chr17-30210571-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 891507.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd at 172 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC6A4	NM_001045.6	c.1393T>C	p.Phe465Leu	missense_variant	11/15	ENST00000650711.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC6A4	ENST00000650711.1	c.1393T>C	p.Phe465Leu	missense_variant	11/15		NM_001045.6	P1

Frequencies

GnomAD3 genomes AF: 0.00113 AC: 172 AN: 152044 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00403

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000958

GnomAD3 exomes AF: 0.000307 AC: 77 AN: 251136 Hom.: 0 AF XY: 0.000302 AC XY: 41 AN XY: 135734

Gnomad AFR exome AF: 0.00437

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000131 AC: 191 AN: 1461732 Hom.: 0 Cov.: 31 AF XY: 0.000129 AC XY: 94 AN XY: 727156

Gnomad4 AFR exome AF: 0.00448

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000207

Gnomad4 OTH exome AF: 0.000248

GnomAD4 genome AF: 0.00113 AC: 172 AN: 152162 Hom.: 0 Cov.: 32 AF XY: 0.00125 AC XY: 93 AN XY: 74394

Gnomad4 AFR AF: 0.00402

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000948

Alfa AF: 0.000531 Hom.: 0

Bravo AF: 0.00120

ESP6500AA AF: 0.00431 AC: 19

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000379 AC: 46

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Behavior disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 28, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

SLC6A4-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 27, 2020

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.77
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.27
Cadd	Benign	15
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.53	D;D;T
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.093
FATHMM_MKL	Pathogenic	0.98	D
MetaRNN	Benign	0.012	T;T;T
MetaSVM	Benign	-0.81	T
MutationAssessor	Benign	0.84	L;L;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.60	T
PROVEAN	Pathogenic	-5.0	D;D;D
REVEL	Benign	0.21
Sift	Benign	0.039	D;D;T
Sift4G	Benign	0.15	T;T;T
Polyphen		0.0090	B;B;.
Vest4		0.37
MutPred		0.27		Loss of methylation at K460 (P = 0.1137);Loss of methylation at K460 (P = 0.1137);Loss of methylation at K460 (P = 0.1137);
MVP		0.36
MPC		0.53
ClinPred		0.076	T
GERP RS		5.0
Varity_R		0.72
gMVP		0.61

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: rs28914833; hg19: chr17-28537589;