NM_001045.6:c.-220-45C>A

Variant names:

• chr17-30222960-G-T
• rs25528
• NM_001045.6:c.-220-45C>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001045.6(SLC6A4):​c.-220-45C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.793 in 685,978 control chromosomes in the GnomAD database, including 218,734 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.

• Frequency:
  • Genomes: 𝑓 0.72 (41171 hom., cov: 32)
  • Exomes 𝑓: 0.81 (177563 hom.)
• Consequence: SLC6A4 NM_001045.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.23
• Publications: 21 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.868 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.-220-45C>A		intron	N/A	NP_001036.1	P31645-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC6A4	ENST00000650711.1	MANE Select	c.-220-45C>A		intron	N/A	ENSP00000498537.1	P31645-1
	SLC6A4	ENST00000261707.7	TSL:1	c.-220-45C>A		intron	N/A	ENSP00000261707.3	P31645-1
	SLC6A4	ENST00000394821.2	TSL:1	c.-220-45C>A		intron	N/A	ENSP00000378298.2	J3KPR9

Frequencies

GnomAD3 genomes AF: 0.719 AC: 109204 AN: 151934 Hom.: 41160 Cov.: 32

Gnomad AFR AF: 0.460

Gnomad AMI AF: 0.906

Gnomad AMR AF: 0.810

Gnomad ASJ AF: 0.830

Gnomad EAS AF: 0.888

Gnomad SAS AF: 0.821

Gnomad FIN AF: 0.818

Gnomad MID AF: 0.778

Gnomad NFE AF: 0.810

Gnomad OTH AF: 0.744

GnomAD4 exome AF: 0.814 AC: 434431 AN: 533926 Hom.: 177563 Cov.: 7 AF XY: 0.814 AC XY: 228668 AN XY: 280788

African (AFR) AF: 0.473 AC: 5743 AN: 12152

American (AMR) AF: 0.855 AC: 23373 AN: 27324

Ashkenazi Jewish (ASJ) AF: 0.830 AC: 9914 AN: 11946

East Asian (EAS) AF: 0.880 AC: 8962 AN: 10182

South Asian (SAS) AF: 0.816 AC: 51858 AN: 63544

European-Finnish (FIN) AF: 0.831 AC: 14291 AN: 17192

Middle Eastern (MID) AF: 0.798 AC: 2279 AN: 2856

European-Non Finnish (NFE) AF: 0.819 AC: 300916 AN: 367450

Other (OTH) AF: 0.803 AC: 17095 AN: 21280

GnomAD4 genome AF: 0.718 AC: 109243 AN: 152052 Hom.: 41171 Cov.: 32 AF XY: 0.724 AC XY: 53763 AN XY: 74306

African (AFR) AF: 0.459 AC: 19035 AN: 41432

American (AMR) AF: 0.810 AC: 12385 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.830 AC: 2882 AN: 3472

East Asian (EAS) AF: 0.889 AC: 4592 AN: 5164

South Asian (SAS) AF: 0.820 AC: 3956 AN: 4824

European-Finnish (FIN) AF: 0.818 AC: 8648 AN: 10566

Middle Eastern (MID) AF: 0.796 AC: 234 AN: 294

European-Non Finnish (NFE) AF: 0.811 AC: 55117 AN: 68002

Other (OTH) AF: 0.746 AC: 1568 AN: 2102

Alfa AF: 0.703 Hom.: 6695

Bravo AF: 0.708

Asia WGS AF: 0.811 AC: 2819 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	9.1
DANN	Benign	0.50
PhyloP100		2.2
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs25528; hg19: chr17-28549978; COSMIC: COSV55566423;