rs28914826

Positions:

• chr17-30235480-C-T

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.-221+133G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0132 in 152,324 control chromosomes in the GnomAD database, including 61 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 0.013 (61 hom., cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SLC6A4 NM_001045.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.153

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=-0.73).
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0132 (2010/152324) while in subpopulation AFR AF= 0.0462 (1922/41576). AF 95% confidence interval is 0.0445. There are 61 homozygotes in gnomad4. There are 964 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 2010 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	UniProt
SLC6A4	NM_001045.6	c.-221+133G>A		intron_variant		ENST00000650711.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC6A4	ENST00000650711.1	c.-221+133G>A		intron_variant			NM_001045.6	P1
SLC6A4	ENST00000261707.7	c.-221+133G>A		intron_variant		1		P1
SLC6A4	ENST00000394821.2	c.-221+133G>A		intron_variant		1
SLC6A4	ENST00000401766.6	c.-124+133G>A		intron_variant		5		P1

Frequencies

GnomAD3 genomes AF: 0.0132 AC: 2009 AN: 152206 Hom.: 61 Cov.: 32

Gnomad AFR AF: 0.0463

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00419

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00765

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 32 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 30

Gnomad4 EAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

GnomAD4 genome AF: 0.0132 AC: 2010 AN: 152324 Hom.: 61 Cov.: 32 AF XY: 0.0129 AC XY: 964 AN XY: 74490

Gnomad4 AFR AF: 0.0462

Gnomad4 AMR AF: 0.00418

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00757

Alfa AF: 0.00957 Hom.: 7

Bravo AF: 0.0146

Asia WGS AF: 0.00289 AC: 10 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	8.7
DANN	Benign	0.92

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: rs28914826; hg19: chr17-28562498;