chr17-30215528-G-A

Variant names:

• chr17-30215528-G-A
• rs28914829
• NM_001045.6:c.1076+83C>T

Variant summary

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

The ENST00000650711.1(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 ENST00000650711.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.140
• Publications: 1 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=-0.91).
• 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 the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000650711.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC6A4	NM_001045.6	MANE Select	c.1076+83C>T		intron	N/A	NP_001036.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC6A4	ENST00000650711.1	MANE Select	c.1076+83C>T		intron	N/A	ENSP00000498537.1
	SLC6A4	ENST00000261707.7	TSL:1	c.1076+83C>T		intron	N/A	ENSP00000261707.3
	SLC6A4	ENST00000394821.2	TSL:1	c.1076+83C>T		intron	N/A	ENSP00000378298.2

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

African (AFR) AF: 0.00784 AC: 190 AN: 24226

American (AMR) AF: 0.0119 AC: 523 AN: 43826

Ashkenazi Jewish (ASJ) AF: 0.0410 AC: 934 AN: 22788

East Asian (EAS) AF: 0.0000798 AC: 3 AN: 37582

South Asian (SAS) AF: 0.00514 AC: 391 AN: 76046

European-Finnish (FIN) AF: 0.0167 AC: 878 AN: 52664

Middle Eastern (MID) AF: 0.00780 AC: 38 AN: 4874

European-Non Finnish (NFE) AF: 0.0348 AC: 23651 AN: 678810

Other (OTH) AF: 0.0257 AC: 1149 AN: 44640

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

African (AFR) AF: 0.00827 AC: 344 AN: 41586

American (AMR) AF: 0.0167 AC: 255 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0409 AC: 142 AN: 3470

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5188

South Asian (SAS) AF: 0.00414 AC: 20 AN: 4830

European-Finnish (FIN) AF: 0.0141 AC: 150 AN: 10618

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.0319 AC: 2171 AN: 68022

Other (OTH) AF: 0.0203 AC: 43 AN: 2114

Alfa AF: 0.0292 Hom.: 93

Bravo AF: 0.0210

Asia WGS AF: 0.00318 AC: 11 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	1.3
DANN	Benign	0.64
PhyloP100		0.14
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs28914829; hg19: chr17-28542546;