rs41274284

Variant names:

• chr17-30217298-G-A
• rs41274284
• NM_001045.6:c.705C>T

Your query was ambiguous. Multiple possible variants found:

• chr17-30217298-G-A
• chr17-30217298-G-C

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Strong BP6 BP7 BS2_Supporting

The NM_001045.6(SLC6A4):​c.705C>T​(p.His235His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00116 in 1,613,686 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0035 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00092 (6 hom.)
• Consequence: SLC6A4 NM_001045.6 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -1.72
• 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):

• autism spectrum disorder

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -7 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.62).
• BP6: Variant 17-30217298-G-A is Benign according to our data. Variant chr17-30217298-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 708975.
• BP7: Synonymous conserved (PhyloP=-1.72 with no splicing effect.
• BS2: High AC in GnomAd4 at 531 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.705C>T	p.His235His	synonymous	Exon 6 of 15	NP_001036.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC6A4	ENST00000650711.1	MANE Select	c.705C>T	p.His235His	synonymous	Exon 6 of 15	ENSP00000498537.1
	SLC6A4	ENST00000261707.7	TSL:1	c.705C>T	p.His235His	synonymous	Exon 6 of 15	ENSP00000261707.3
	SLC6A4	ENST00000394821.2	TSL:1	c.705C>T	p.His235His	synonymous	Exon 6 of 15	ENSP00000378298.2

Frequencies

GnomAD3 genomes AF: 0.00348 AC: 530 AN: 152216 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0104

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00308

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000588

Gnomad OTH AF: 0.00382

GnomAD2 exomes AF: 0.00127 AC: 318 AN: 250210 AF XY: 0.00126

Gnomad AFR exome AF: 0.00918

Gnomad AMR exome AF: 0.00134

Gnomad ASJ exome AF: 0.000100

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000463

Gnomad NFE exome AF: 0.000797

Gnomad OTH exome AF: 0.00198

GnomAD4 exome AF: 0.000922 AC: 1347 AN: 1461352 Hom.: 6 Cov.: 31 AF XY: 0.000945 AC XY: 687 AN XY: 727004

African (AFR) AF: 0.0109 AC: 365 AN: 33442

American (AMR) AF: 0.00193 AC: 86 AN: 44626

Ashkenazi Jewish (ASJ) AF: 0.000153 AC: 4 AN: 26088

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.000545 AC: 47 AN: 86184

European-Finnish (FIN) AF: 0.0000375 AC: 2 AN: 53396

Middle Eastern (MID) AF: 0.00850 AC: 49 AN: 5764

European-Non Finnish (NFE) AF: 0.000590 AC: 656 AN: 1111790

Other (OTH) AF: 0.00227 AC: 137 AN: 60362

GnomAD4 genome AF: 0.00349 AC: 531 AN: 152334 Hom.: 1 Cov.: 32 AF XY: 0.00329 AC XY: 245 AN XY: 74492

African (AFR) AF: 0.0104 AC: 431 AN: 41570

American (AMR) AF: 0.00301 AC: 46 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.000588 AC: 40 AN: 68024

Other (OTH) AF: 0.00378 AC: 8 AN: 2114

Alfa AF: 0.00194 Hom.: 0

Bravo AF: 0.00433

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.00147

EpiControl AF: 0.00107

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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	-0.62
CADD	Benign	2.5
DANN	Benign	0.41
PhyloP100		-1.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs41274284; hg19: chr17-28544316;