5-1406260-C-G

Variant names:

• chr5-1406260-C-G
• rs6880875
• NM_001044.5:c.1527G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001044.5(SLC6A3):​c.1527G>C​(p.Gln509His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. Q509Q) has been classified as Benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: SLC6A3 NM_001044.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0850
• Publications: 0 publications found

Genes affected

SLC6A3 (HGNC:11049): (solute carrier family 6 member 3) This gene encodes a dopamine transporter which is a member of the sodium- and chloride-dependent neurotransmitter transporter family. The 3' UTR of this gene contains a 40 bp tandem repeat, referred to as a variable number tandem repeat or VNTR, which can be present in 3 to 11 copies. Variation in the number of repeats is associated with idiopathic epilepsy, attention-deficit hyperactivity disorder, dependence on alcohol and cocaine, susceptibility to Parkinson disease and protection against nicotine dependence.[provided by RefSeq, Nov 2009]

SLC6A3 Gene-Disease associations (from GenCC):

• classic dopamine transporter deficiency syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• SLC6A3-related dopamine transporter deficiency syndrome

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• parkinsonism-dystonia, infantile

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12777501).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001044.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC6A3	NM_001044.5	MANE Select	c.1527G>C	p.Gln509His	missense	Exon 12 of 15	NP_001035.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC6A3	ENST00000270349.12	TSL:1 MANE Select	c.1527G>C	p.Gln509His	missense	Exon 12 of 15	ENSP00000270349.9
	SLC6A3	ENST00000941790.1		c.1392G>C	p.Gln464His	missense	Exon 11 of 14	ENSP00000611849.1
	SLC6A3	ENST00000713696.1		c.1392G>C	p.Gln464His	missense	Exon 11 of 15	ENSP00000519000.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Parkinsonism-dystonia, infantile (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Benign	0.24	T
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.49
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.80	T
M_CAP	Uncertain	0.090	D
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	1.5	L
PhyloP100		-0.085
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.13
Sift	Uncertain	0.016	D
Sift4G	Uncertain	0.034	D
Polyphen		0.0010	B
Vest4		0.081
MutPred		0.48		Gain of glycosylation at S505 (P = 0.1347)
MVP		0.67
MPC		0.57
ClinPred		0.18	T
GERP RS		-0.60
Varity_R		0.23
gMVP		0.44
Mutation Taster		=84/16	polymorphism

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: rs6880875; hg19: chr5-1406375;