17-30222940-C-T

Position:

• chr17-30222940-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.-220-25G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0144 in 854,130 control chromosomes in the GnomAD database, including 132 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. There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.010 (15 hom., cov: 33)
  • Exomes 𝑓: 0.015 (117 hom.)
• Consequence: SLC6A4 NM_001045.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.824

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: This place is a probable branch point but likely benign (scored 3 / 10). Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00996 (1516/152248) while in subpopulation SAS AF= 0.0184 (89/4828). AF 95% confidence interval is 0.0153. There are 15 homozygotes in gnomad4. There are 705 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1516 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.-220-25G>A		intron_variant		ENST00000650711.1	NP_001036.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC6A4	ENST00000650711.1	c.-220-25G>A		intron_variant			NM_001045.6	ENSP00000498537	P1
SLC6A4	ENST00000261707.7	c.-220-25G>A		intron_variant		1		ENSP00000261707	P1
SLC6A4	ENST00000394821.2	c.-220-25G>A		intron_variant		1		ENSP00000378298
SLC6A4	ENST00000401766.6	c.-123-859G>A		intron_variant		5		ENSP00000385822	P1

Frequencies

GnomAD3 genomes AF: 0.00995 AC: 1513 AN: 152130 Hom.: 14 Cov.: 33

Gnomad AFR AF: 0.00302

Gnomad AMI AF: 0.00330

Gnomad AMR AF: 0.00426

Gnomad ASJ AF: 0.0242

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0178

Gnomad FIN AF: 0.00669

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0154

Gnomad OTH AF: 0.0124

GnomAD4 exome AF: 0.0153 AC: 10763 AN: 701882 Hom.: 117 Cov.: 9 AF XY: 0.0155 AC XY: 5596 AN XY: 360610

Gnomad4 AFR exome AF: 0.00290

Gnomad4 AMR exome AF: 0.00389

Gnomad4 ASJ exome AF: 0.0211

Gnomad4 EAS exome AF: 0.000181

Gnomad4 SAS exome AF: 0.0213

Gnomad4 FIN exome AF: 0.00889

Gnomad4 NFE exome AF: 0.0160

Gnomad4 OTH exome AF: 0.0159

GnomAD4 genome AF: 0.00996 AC: 1516 AN: 152248 Hom.: 15 Cov.: 33 AF XY: 0.00947 AC XY: 705 AN XY: 74438

Gnomad4 AFR AF: 0.00301

Gnomad4 AMR AF: 0.00425

Gnomad4 ASJ AF: 0.0242

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.0184

Gnomad4 FIN AF: 0.00669

Gnomad4 NFE AF: 0.0154

Gnomad4 OTH AF: 0.0123

Alfa AF: 0.00597 Hom.: 1

Bravo AF: 0.00926

Asia WGS AF: 0.0100 AC: 35 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	4.9
DANN	Benign	0.48
BranchPoint Hunter		3.0

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: rs2020941; hg19: chr17-28549958;