chr17-30222880-G-T

Variant names:

• chr17-30222880-G-T
• rs6354
• NM_001045.6:c.-185C>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001045.6(SLC6A4):​c.-185C>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.806 in 1,299,148 control chromosomes in the GnomAD database, including 422,562 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.78 (46989 hom., cov: 33)
  • Exomes 𝑓: 0.81 (375573 hom.)
• Consequence: SLC6A4 NM_001045.6 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.543
• Publications: 65 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 17-30222880-G-T is Benign according to our data. Variant chr17-30222880-G-T is described in ClinVar as Likely_benign. ClinVar VariationId is 322546.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.866 is higher than 0.05.

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.-185C>A		5_prime_UTR	Exon 2 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.-185C>A		5_prime_UTR	Exon 2 of 15	ENSP00000498537.1	P31645-1
	SLC6A4	ENST00000261707.7	TSL:1	c.-185C>A		5_prime_UTR	Exon 2 of 15	ENSP00000261707.3	P31645-1
	SLC6A4	ENST00000394821.2	TSL:1	c.-185C>A		5_prime_UTR	Exon 2 of 15	ENSP00000378298.2	J3KPR9

Frequencies

GnomAD3 genomes AF: 0.784 AC: 119208 AN: 152102 Hom.: 46974 Cov.: 33

Gnomad AFR AF: 0.685

Gnomad AMI AF: 0.908

Gnomad AMR AF: 0.834

Gnomad ASJ AF: 0.832

Gnomad EAS AF: 0.886

Gnomad SAS AF: 0.823

Gnomad FIN AF: 0.818

Gnomad MID AF: 0.820

Gnomad NFE AF: 0.812

Gnomad OTH AF: 0.784

GnomAD4 exome AF: 0.809 AC: 927348 AN: 1146928 Hom.: 375573 Cov.: 24 AF XY: 0.809 AC XY: 455059 AN XY: 562700

African (AFR) AF: 0.673 AC: 16333 AN: 24252

American (AMR) AF: 0.867 AC: 24491 AN: 28264

Ashkenazi Jewish (ASJ) AF: 0.829 AC: 13201 AN: 15916

East Asian (EAS) AF: 0.877 AC: 11372 AN: 12966

South Asian (SAS) AF: 0.815 AC: 62019 AN: 76100

European-Finnish (FIN) AF: 0.835 AC: 22807 AN: 27328

Middle Eastern (MID) AF: 0.810 AC: 3561 AN: 4396

European-Non Finnish (NFE) AF: 0.808 AC: 740332 AN: 916286

Other (OTH) AF: 0.802 AC: 33232 AN: 41420

GnomAD4 genome AF: 0.784 AC: 119270 AN: 152220 Hom.: 46989 Cov.: 33 AF XY: 0.786 AC XY: 58512 AN XY: 74422

African (AFR) AF: 0.684 AC: 28415 AN: 41528

American (AMR) AF: 0.834 AC: 12759 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.832 AC: 2885 AN: 3468

East Asian (EAS) AF: 0.887 AC: 4594 AN: 5178

South Asian (SAS) AF: 0.822 AC: 3972 AN: 4832

European-Finnish (FIN) AF: 0.818 AC: 8670 AN: 10596

Middle Eastern (MID) AF: 0.833 AC: 245 AN: 294

European-Non Finnish (NFE) AF: 0.812 AC: 55247 AN: 68010

Other (OTH) AF: 0.785 AC: 1657 AN: 2110

Alfa AF: 0.806 Hom.: 79030

Bravo AF: 0.782

Asia WGS AF: 0.827 AC: 2874 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	-0.84
CADD	Benign	0.74
DANN	Benign	0.52
PhyloP100		-0.54
Mutation Taster		=299/1	polymorphism (auto)

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: rs6354; hg19: chr17-28549898;