17-30195008-C-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001045.6(SLC6A4):c.*3448G>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.017 in 152,282 control chromosomes in the GnomAD database, including 32 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.017 (32 hom., cov: 32)
  • Failed GnomAD Quality Control
• Consequence: SLC6A4 NM_001045.6 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.337

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=-0.76).
• BP6: Variant 17-30195008-C-G is Benign according to our data. Variant chr17-30195008-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 889814.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.017 (2591/152282) while in subpopulation NFE AF= 0.0249 (1697/68020). AF 95% confidence interval is 0.024. There are 32 homozygotes in gnomad4. There are 1276 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 2592 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC6A4	NM_001045.6	c.*3448G>C		3_prime_UTR_variant	15/15	ENST00000650711.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC6A4	ENST00000650711.1	c.*3448G>C		3_prime_UTR_variant	15/15		NM_001045.6	P1
SLC6A4	ENST00000261707.7	c.*3448G>C		3_prime_UTR_variant	15/15	1		P1
SLC6A4	ENST00000401766.6	c.*3448G>C		3_prime_UTR_variant	14/14	5		P1

Frequencies

GnomAD3 genomes AF: 0.0170 AC: 2592 AN: 152164 Hom.: 32 Cov.: 32

Gnomad AFR AF: 0.00403

Gnomad AMI AF: 0.0186

Gnomad AMR AF: 0.0211

Gnomad ASJ AF: 0.0141

Gnomad EAS AF: 0.000384

Gnomad SAS AF: 0.00620

Gnomad FIN AF: 0.0231

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0250

Gnomad OTH AF: 0.0248

GnomAD4 exome Data not reliable, filtered out with message: AC0 AC: 0 AN: 0 Hom.: 0 Cov.: 0 AC XY: 0 AN XY: 0

GnomAD4 genome AF: 0.0170 AC: 2591 AN: 152282 Hom.: 32 Cov.: 32 AF XY: 0.0171 AC XY: 1276 AN XY: 74470

Gnomad4 AFR AF: 0.00402

Gnomad4 AMR AF: 0.0211

Gnomad4 ASJ AF: 0.0141

Gnomad4 EAS AF: 0.000385

Gnomad4 SAS AF: 0.00621

Gnomad4 FIN AF: 0.0231

Gnomad4 NFE AF: 0.0249

Gnomad4 OTH AF: 0.0246

Alfa AF: 0.00948 Hom.: 3

Bravo AF: 0.0163

Asia WGS AF: 0.00346 AC: 12 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Behavior disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
Cadd	Benign	2.2
Dann	Benign	0.85

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: rs62068662; hg19: chr17-28522026;