rs13306796

Variant names:

• chr17-30198128-T-C
• rs13306796
• NM_001045.6:c.*328A>G

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_Moderate BP6_Very_Strong BS1 BS2_Supporting

The NM_001045.6(SLC6A4):​c.*328A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00129 in 274,566 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00096 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0017 (2 hom.)
• Consequence: SLC6A4 NM_001045.6 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.273
• Publications: 2 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):

• obsessive-compulsive disorder

  Inheritance: AD Classification: LIMITED Submitted by: PanelApp Australia
• autism spectrum disorder

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.37).
• BP6: Variant 17-30198128-T-C is Benign according to our data. Variant chr17-30198128-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 889946.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000958 (146/152332) while in subpopulation EAS AF = 0.0235 (122/5184). AF 95% confidence interval is 0.0201. There are 0 homozygotes in GnomAd4. There are 83 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 146 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: NM_001045.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC6A4	NM_001045.6	MANE Select	c.*328A>G		3_prime_UTR	Exon 15 of 15	NP_001036.1	P31645-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC6A4	ENST00000650711.1	MANE Select	c.*328A>G		3_prime_UTR	Exon 15 of 15	ENSP00000498537.1	P31645-1
	SLC6A4	ENST00000261707.7	TSL:1	c.*328A>G		3_prime_UTR	Exon 15 of 15	ENSP00000261707.3	P31645-1
	SLC6A4	ENST00000579221.5	TSL:1	n.*645A>G		non_coding_transcript_exon	Exon 5 of 5	ENSP00000463172.1	J3QKP3

Frequencies

GnomAD3 genomes AF: 0.000992 AC: 151 AN: 152214 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0241

Gnomad SAS AF: 0.00290

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00143

GnomAD4 exome AF: 0.00169 AC: 207 AN: 122234 Hom.: 2 Cov.: 0 AF XY: 0.00167 AC XY: 103 AN XY: 61690

African (AFR) AF: 0.00 AC: 0 AN: 4112

American (AMR) AF: 0.00 AC: 0 AN: 4008

Ashkenazi Jewish (ASJ) AF: 0.000205 AC: 1 AN: 4888

East Asian (EAS) AF: 0.0194 AC: 192 AN: 9894

South Asian (SAS) AF: 0.000519 AC: 1 AN: 1926

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8982

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 652

European-Non Finnish (NFE) AF: 0.0000505 AC: 4 AN: 79172

Other (OTH) AF: 0.00105 AC: 9 AN: 8600

GnomAD4 genome AF: 0.000958 AC: 146 AN: 152332 Hom.: 0 Cov.: 32 AF XY: 0.00111 AC XY: 83 AN XY: 74496

African (AFR) AF: 0.0000962 AC: 4 AN: 41572

American (AMR) AF: 0.0000654 AC: 1 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.0235 AC: 122 AN: 5184

South Asian (SAS) AF: 0.00269 AC: 13 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

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

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68034

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.000182 Hom.: 0

Bravo AF: 0.00129

Asia WGS AF: 0.0120 AC: 43 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Behavior disorder (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.37
CADD	Benign	9.7
DANN	Benign	0.78
PhyloP100		-0.27

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: rs13306796; hg19: chr17-28525146;