rs28914827

Variant names:

• chr17-30222791-C-T
• rs28914827
• NM_001045.6:c.-124+28G>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BS1 BS2_Supporting

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
• Publications: 3 publications found

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]

SLC6A4 Gene-Disease associations (from GenCC):

• autism spectrum disorder

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -9 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1739 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 rank	MANE	Protein	UniProt
SLC6A4	NM_001045.6	c.-124+28G>A		intron_variant	Intron 2 of 14	ENST00000650711.1	NP_001036.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC6A4	ENST00000650711.1	c.-124+28G>A		intron_variant	Intron 2 of 14		NM_001045.6	ENSP00000498537.1
SLC6A4	ENST00000261707.7	c.-124+28G>A		intron_variant	Intron 2 of 14	1		ENSP00000261707.3
SLC6A4	ENST00000394821.2	c.-124+28G>A		intron_variant	Intron 2 of 14	1		ENSP00000378298.2
SLC6A4	ENST00000401766.6	c.-123-710G>A		intron_variant	Intron 1 of 13	5		ENSP00000385822.2

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

GnomAD2 exomes AF: 0.0116 AC: 1782 AN: 153340 AF XY: 0.0120

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 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

African (AFR) AF: 0.00209 AC: 51 AN: 24404

American (AMR) AF: 0.00513 AC: 145 AN: 28268

Ashkenazi Jewish (ASJ) AF: 0.00257 AC: 41 AN: 15940

East Asian (EAS) AF: 0.000385 AC: 5 AN: 12980

South Asian (SAS) AF: 0.0101 AC: 772 AN: 76188

European-Finnish (FIN) AF: 0.00702 AC: 194 AN: 27636

Middle Eastern (MID) AF: 0.00363 AC: 16 AN: 4404

European-Non Finnish (NFE) AF: 0.0218 AC: 20078 AN: 920520

Other (OTH) AF: 0.0148 AC: 615 AN: 41616

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

African (AFR) AF: 0.00385 AC: 160 AN: 41582

American (AMR) AF: 0.00536 AC: 82 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00259 AC: 9 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00972 AC: 47 AN: 4834

European-Finnish (FIN) AF: 0.00659 AC: 70 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0197 AC: 1340 AN: 68026

Other (OTH) AF: 0.0118 AC: 25 AN: 2116

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
PhyloP100		-0.45
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs28914827; hg19: chr17-28549809;