chr17-30211356-T-G

Position:

• chr17-30211356-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001045.6(SLC6A4):​c.1273A>C​(p.Ile425Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,410 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SLC6A4 NM_001045.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.23

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.26569745).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC6A4	NM_001045.6	c.1273A>C	p.Ile425Leu	missense_variant	10/15	ENST00000650711.1	NP_001036.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC6A4	ENST00000650711.1	c.1273A>C	p.Ile425Leu	missense_variant	10/15		NM_001045.6	ENSP00000498537	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461410 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 727038

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.0
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.24	T;T;T
Eigen	Benign	-0.0021
Eigen_PC	Benign	0.17
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.93	.;D;D
M_CAP	Benign	0.025	T
MetaRNN	Benign	0.27	T;T;T
MetaSVM	Benign	-0.62	T
MutationAssessor	Uncertain	2.1	M;M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.79	T
PROVEAN	Benign	-1.1	N;N;.
REVEL	Uncertain	0.31
Sift	Benign	0.34	T;T;.
Sift4G	Benign	0.34	T;T;T
Polyphen		0.010	B;B;.
Vest4		0.60
MutPred		0.19		Loss of glycosylation at T421 (P = 0.2441);Loss of glycosylation at T421 (P = 0.2441);Loss of glycosylation at T421 (P = 0.2441);
MVP		0.61
MPC		0.51
ClinPred		0.76	D
GERP RS		5.2
Varity_R		0.63
gMVP		0.51

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: rs28914832; hg19: chr17-28538374;