rs28914829

Positions:

• chr17-30215528-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BS1 BS2_Supporting

The NM_001045.6(SLC6A4):​c.1076+83C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0272 in 1,137,790 control chromosomes in the GnomAD database, including 534 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.021 (43 hom., cov: 31)
  • Exomes 𝑓: 0.028 (491 hom.)
• Consequence: SLC6A4 NM_001045.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.140

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0206 (3134/152334) while in subpopulation NFE AF= 0.0319 (2171/68022). AF 95% confidence interval is 0.0308. There are 43 homozygotes in gnomad4. There are 1451 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 3134 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.1076+83C>T		intron_variant		ENST00000650711.1	NP_001036.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC6A4	ENST00000650711.1	c.1076+83C>T		intron_variant			NM_001045.6	ENSP00000498537	P1
SLC6A4	ENST00000261707.7	c.1076+83C>T		intron_variant		1		ENSP00000261707	P1
SLC6A4	ENST00000394821.2	c.1076+83C>T		intron_variant		1		ENSP00000378298
SLC6A4	ENST00000401766.6	c.1076+83C>T		intron_variant		5		ENSP00000385822	P1

Frequencies

GnomAD3 genomes AF: 0.0206 AC: 3134 AN: 152216 Hom.: 43 Cov.: 31

Gnomad AFR AF: 0.00830

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0168

Gnomad ASJ AF: 0.0409

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00393

Gnomad FIN AF: 0.0141

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0319

Gnomad OTH AF: 0.0206

GnomAD4 exome AF: 0.0282 AC: 27757 AN: 985456 Hom.: 491 AF XY: 0.0273 AC XY: 13910 AN XY: 510228

Gnomad4 AFR exome AF: 0.00784

Gnomad4 AMR exome AF: 0.0119

Gnomad4 ASJ exome AF: 0.0410

Gnomad4 EAS exome AF: 0.0000798

Gnomad4 SAS exome AF: 0.00514

Gnomad4 FIN exome AF: 0.0167

Gnomad4 NFE exome AF: 0.0348

Gnomad4 OTH exome AF: 0.0257

GnomAD4 genome AF: 0.0206 AC: 3134 AN: 152334 Hom.: 43 Cov.: 31 AF XY: 0.0195 AC XY: 1451 AN XY: 74488

Gnomad4 AFR AF: 0.00827

Gnomad4 AMR AF: 0.0167

Gnomad4 ASJ AF: 0.0409

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.00414

Gnomad4 FIN AF: 0.0141

Gnomad4 NFE AF: 0.0319

Gnomad4 OTH AF: 0.0203

Alfa AF: 0.0278 Hom.: 11

Bravo AF: 0.0210

Asia WGS AF: 0.00318 AC: 11 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	1.3
DANN	Benign	0.64

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: rs28914829; hg19: chr17-28542546;