rs41274284

Positions:

• chr17-30217298-G-A

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_Strong BP6 BP7 BS2_Supporting

The NM_001045.6(SLC6A4):​c.705C>T​(p.His235=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00116 in 1,613,686 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0035 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00092 (6 hom.)
• Consequence: SLC6A4 NM_001045.6 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -1.72

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 -7 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.62).
• BP6: Variant 17-30217298-G-A is Benign according to our data. Variant chr17-30217298-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 708975.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=1}.
• BP7: Synonymous conserved (PhyloP=-1.72 with no splicing effect.
• BS2: High AC in GnomAd4 at 531 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC6A4	NM_001045.6	c.705C>T	p.His235=	synonymous_variant	6/15	ENST00000650711.1	NP_001036.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC6A4	ENST00000650711.1	c.705C>T	p.His235=	synonymous_variant	6/15		NM_001045.6	ENSP00000498537	P1
SLC6A4	ENST00000261707.7	c.705C>T	p.His235=	synonymous_variant	6/15	1		ENSP00000261707	P1
SLC6A4	ENST00000394821.2	c.705C>T	p.His235=	synonymous_variant	6/15	1		ENSP00000378298
SLC6A4	ENST00000401766.6	c.705C>T	p.His235=	synonymous_variant	5/14	5		ENSP00000385822	P1

Frequencies

GnomAD3 genomes AF: 0.00348 AC: 530 AN: 152216 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0104

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00308

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000588

Gnomad OTH AF: 0.00382

GnomAD3 exomes AF: 0.00127 AC: 318 AN: 250210 Hom.: 2 AF XY: 0.00126 AC XY: 170 AN XY: 135330

Gnomad AFR exome AF: 0.00918

Gnomad AMR exome AF: 0.00134

Gnomad ASJ exome AF: 0.000100

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000622

Gnomad FIN exome AF: 0.0000463

Gnomad NFE exome AF: 0.000797

Gnomad OTH exome AF: 0.00198

GnomAD4 exome AF: 0.000922 AC: 1347 AN: 1461352 Hom.: 6 Cov.: 31 AF XY: 0.000945 AC XY: 687 AN XY: 727004

Gnomad4 AFR exome AF: 0.0109

Gnomad4 AMR exome AF: 0.00193

Gnomad4 ASJ exome AF: 0.000153

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000545

Gnomad4 FIN exome AF: 0.0000375

Gnomad4 NFE exome AF: 0.000590

Gnomad4 OTH exome AF: 0.00227

GnomAD4 genome AF: 0.00349 AC: 531 AN: 152334 Hom.: 1 Cov.: 32 AF XY: 0.00329 AC XY: 245 AN XY: 74492

Gnomad4 AFR AF: 0.0104

Gnomad4 AMR AF: 0.00301

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000588

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.00194 Hom.: 0

Bravo AF: 0.00433

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.00147

EpiControl AF: 0.00107

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Behavior disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 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. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 07, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
CADD	Benign	2.5
DANN	Benign	0.41
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs41274284; hg19: chr17-28544316;