chr17-30210569-G-A

Variant names:

• chr17-30210569-G-A
• rs41274280
• NM_001045.6:c.1395C>T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Very_Strong BP7 BS2_Supporting

The NM_001045.6(SLC6A4):​c.1395C>T​(p.Phe465Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000893 in 1,613,868 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0023 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00075 (3 hom.)
• Consequence: SLC6A4 NM_001045.6 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.143

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 17-30210569-G-A is Benign according to our data. Variant chr17-30210569-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 891506.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.143 with no splicing effect.
• BS2: High AC in GnomAd4 at 343 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.1395C>T	p.Phe465Phe	synonymous_variant	Exon 11 of 15	ENST00000650711.1	NP_001036.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC6A4	ENST00000650711.1	c.1395C>T	p.Phe465Phe	synonymous_variant	Exon 11 of 15		NM_001045.6	ENSP00000498537.1

Frequencies

GnomAD3 genomes AF: 0.00226 AC: 343 AN: 152072 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00628

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00236

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000623

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000500

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.000880 AC: 221 AN: 251086 Hom.: 0 AF XY: 0.000936 AC XY: 127 AN XY: 135710

Gnomad AFR exome AF: 0.00462

Gnomad AMR exome AF: 0.000752

Gnomad ASJ exome AF: 0.0000994

Gnomad EAS exome AF: 0.000381

Gnomad SAS exome AF: 0.000588

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000731

Gnomad OTH exome AF: 0.00163

GnomAD4 exome AF: 0.000751 AC: 1098 AN: 1461678 Hom.: 3 Cov.: 31 AF XY: 0.000778 AC XY: 566 AN XY: 727116

Gnomad4 AFR exome AF: 0.00621

Gnomad4 AMR exome AF: 0.00148

Gnomad4 ASJ exome AF: 0.000191

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.000522

Gnomad4 FIN exome AF: 0.0000375

Gnomad4 NFE exome AF: 0.000563

Gnomad4 OTH exome AF: 0.00157

GnomAD4 genome AF: 0.00225 AC: 343 AN: 152190 Hom.: 1 Cov.: 32 AF XY: 0.00210 AC XY: 156 AN XY: 74402

Gnomad4 AFR AF: 0.00626

Gnomad4 AMR AF: 0.00236

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000623

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000500

Gnomad4 OTH AF: 0.00332

Alfa AF: 0.00124 Hom.: 0

Bravo AF: 0.00274

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00136

EpiControl AF: 0.00107

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Behavior disorder Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	0.99
DANN	Benign	0.84

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: rs41274280; hg19: chr17-28537587; COSMIC: COSV99911236; COSMIC: COSV99911236;