rs6355

Positions:

• chr17-30221792-C-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BS1 BS2_Supporting

The NM_001045.6(SLC6A4):​c.167G>C​(p.Gly56Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0174 in 1,614,164 control chromosomes in the GnomAD database, including 310 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict 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: 𝑓 0.011 (23 hom., cov: 32)
  • Exomes 𝑓: 0.018 (287 hom.)
• Consequence: SLC6A4 NM_001045.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.477

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 Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0038065612).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0115 (1745/152280) while in subpopulation NFE AF= 0.0198 (1346/68022). AF 95% confidence interval is 0.0189. There are 23 homozygotes in gnomad4. There are 753 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1745 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC6A4	NM_001045.6	c.167G>C	p.Gly56Ala	missense_variant	3/15	ENST00000650711.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC6A4	ENST00000650711.1	c.167G>C	p.Gly56Ala	missense_variant	3/15		NM_001045.6	P1
SLC6A4	ENST00000261707.7	c.167G>C	p.Gly56Ala	missense_variant	3/15	1		P1
SLC6A4	ENST00000394821.2	c.167G>C	p.Gly56Ala	missense_variant	3/15	1
SLC6A4	ENST00000401766.6	c.167G>C	p.Gly56Ala	missense_variant	2/14	5		P1

Frequencies

GnomAD3 genomes AF: 0.0115 AC: 1744 AN: 152162 Hom.: 23 Cov.: 32

Gnomad AFR AF: 0.00384

Gnomad AMI AF: 0.00659

Gnomad AMR AF: 0.00543

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00954

Gnomad FIN AF: 0.00660

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0198

Gnomad OTH AF: 0.0120

GnomAD3 exomes AF: 0.0120 AC: 3024 AN: 251486 Hom.: 29 AF XY: 0.0122 AC XY: 1661 AN XY: 135918

Gnomad AFR exome AF: 0.00363

Gnomad AMR exome AF: 0.00463

Gnomad ASJ exome AF: 0.00347

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0105

Gnomad FIN exome AF: 0.00693

Gnomad NFE exome AF: 0.0197

Gnomad OTH exome AF: 0.00912

GnomAD4 exome AF: 0.0180 AC: 26274 AN: 1461884 Hom.: 287 Cov.: 33 AF XY: 0.0177 AC XY: 12880 AN XY: 727244

Gnomad4 AFR exome AF: 0.00260

Gnomad4 AMR exome AF: 0.00487

Gnomad4 ASJ exome AF: 0.00314

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.0102

Gnomad4 FIN exome AF: 0.00784

Gnomad4 NFE exome AF: 0.0213

Gnomad4 OTH exome AF: 0.0140

GnomAD4 genome AF: 0.0115 AC: 1745 AN: 152280 Hom.: 23 Cov.: 32 AF XY: 0.0101 AC XY: 753 AN XY: 74446

Gnomad4 AFR AF: 0.00383

Gnomad4 AMR AF: 0.00542

Gnomad4 ASJ AF: 0.00259

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00976

Gnomad4 FIN AF: 0.00660

Gnomad4 NFE AF: 0.0198

Gnomad4 OTH AF: 0.0118

Alfa AF: 0.0167 Hom.: 18

Bravo AF: 0.0109

TwinsUK AF: 0.0227 AC: 84

ALSPAC AF: 0.0265 AC: 102

ESP6500AA AF: 0.00545 AC: 24

ESP6500EA AF: 0.0215 AC: 185

ExAC AF: 0.0123 AC: 1499

Asia WGS AF: 0.00346 AC: 12 AN: 3478

EpiCase AF: 0.0187

EpiControl AF: 0.0167

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	7.5
DANN	Benign	0.89
DEOGEN2	Benign	0.18	T;T;T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.70	.;T;T
MetaRNN	Benign	0.0038	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.55	N;N;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.2	N;N;.
REVEL	Benign	0.10
Sift	Uncertain	0.018	D;D;.
Sift4G	Benign	0.23	T;T;T
Polyphen		0.0	B;B;.
Vest4		0.040
MPC		0.48
ClinPred		0.0028	T
GERP RS		0.70
Varity_R		0.049
gMVP		0.30

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: rs6355; hg19: chr17-28548810;