rs28914827

chr17-30222791-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_001045.6(SLC6A4):c.-124+28G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0181 in 1,304,300 control chromosomes in the GnomAD database, including 266 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 0.011 (22 hom., cov: 32)
  • Exomes 𝑓: 0.019 (244 hom.)
• Consequence: SLC6A4 NM_001045.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.453

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0114 (1739/152344) while in subpopulation NFE AF= 0.0197 (1340/68026). AF 95% confidence interval is 0.0188. There are 22 homozygotes in gnomad4. There are 749 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 1738 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC6A4	NM_001045.6	c.-124+28G>A		intron_variant		ENST00000650711.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC6A4	ENST00000650711.1	c.-124+28G>A		intron_variant			NM_001045.6	P1
SLC6A4	ENST00000261707.7	c.-124+28G>A		intron_variant		1		P1
SLC6A4	ENST00000394821.2	c.-124+28G>A		intron_variant		1
SLC6A4	ENST00000401766.6	c.-123-710G>A		intron_variant		5		P1

Frequencies

GnomAD3 genomes AF: 0.0114 AC: 1738 AN: 152226 Hom.: 22 Cov.: 32

Gnomad AFR AF: 0.00386

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.00536

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00951

Gnomad FIN AF: 0.00659

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0197

Gnomad OTH AF: 0.0119

GnomAD3 exomes AF: 0.0116 AC: 1782 AN: 153340 Hom.: 15 AF XY: 0.0120 AC XY: 981 AN XY: 82046

Gnomad AFR exome AF: 0.00312

Gnomad AMR exome AF: 0.00504

Gnomad ASJ exome AF: 0.00344

Gnomad EAS exome AF: 0.000538

Gnomad SAS exome AF: 0.0108

Gnomad FIN exome AF: 0.00629

Gnomad NFE exome AF: 0.0208

Gnomad OTH exome AF: 0.00894

GnomAD4 exome AF: 0.0190 AC: 21917 AN: 1151956 Hom.: 244 Cov.: 30 AF XY: 0.0188 AC XY: 10617 AN XY: 564880

Gnomad4 AFR exome AF: 0.00209

Gnomad4 AMR exome AF: 0.00513

Gnomad4 ASJ exome AF: 0.00257

Gnomad4 EAS exome AF: 0.000385

Gnomad4 SAS exome AF: 0.0101

Gnomad4 FIN exome AF: 0.00702

Gnomad4 NFE exome AF: 0.0218

Gnomad4 OTH exome AF: 0.0148

GnomAD4 genome AF: 0.0114 AC: 1739 AN: 152344 Hom.: 22 Cov.: 32 AF XY: 0.0101 AC XY: 749 AN XY: 74498

Gnomad4 AFR AF: 0.00385

Gnomad4 AMR AF: 0.00536

Gnomad4 ASJ AF: 0.00259

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00972

Gnomad4 FIN AF: 0.00659

Gnomad4 NFE AF: 0.0197

Gnomad4 OTH AF: 0.0118

Alfa AF: 0.0128 Hom.: 3

Bravo AF: 0.0109

Asia WGS AF: 0.00346 AC: 12 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
Cadd	Benign	1.5
Dann	Benign	0.44

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: rs28914827; hg19: chr17-28549809;