rs138085358

chr5-36686136-G-A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4 BS2

The NM_004172.5(SLC1A3):c.1496G>A(p.Arg499Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000123 in 1,614,124 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00013 (0 hom.)
• Consequence: SLC1A3 NM_004172.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:5 B:1
• Conservation: PhyloP100: 6.49

Genes affected

SLC1A3 (HGNC:10941): (solute carrier family 1 member 3) This gene encodes a member of a member of a high affinity glutamate transporter family. This gene functions in the termination of excitatory neurotransmission in central nervous system. Mutations are associated with episodic ataxia, Type 6. Alternative splicing results in multiple transcript variants.[provided by RefSeq, Feb 2014]

SLC1A3-AS1 (HGNC:56374): (SLC1A3 antisense RNA 1)

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.27596408).
• BS2: High AC in GnomAd at 10 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC1A3	NM_004172.5	c.1496G>A	p.Arg499Gln	missense_variant	10/10	ENST00000265113.9
SLC1A3-AS1	XR_007058736.1	n.76-17425C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC1A3	ENST00000265113.9	c.1496G>A	p.Arg499Gln	missense_variant	10/10	1	NM_004172.5	P1
SLC1A3-AS1	ENST00000510740.1	n.61-17425C>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.0000657 AC: 10 AN: 152166 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000795 AC: 20 AN: 251472 Hom.: 0 AF XY: 0.0000956 AC XY: 13 AN XY: 135916

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000141

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000129 AC: 189 AN: 1461840 Hom.: 0 Cov.: 32 AF XY: 0.000122 AC XY: 89 AN XY: 727230

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000157

Gnomad4 OTH exome AF: 0.000182

GnomAD4 genome AF: 0.0000657 AC: 10 AN: 152284 Hom.: 0 Cov.: 33 AF XY: 0.0000671 AC XY: 5 AN XY: 74472

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000154 Hom.: 0

Bravo AF: 0.0000793

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.0000906 AC: 11

EpiCase AF: 0.00

EpiControl AF: 0.000296

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:5 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Episodic ataxia type 6 Pathogenic:1 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 02, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jan 01, 2019	- -

not provided Uncertain:2 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2023	SLC1A3: BS1 -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Oct 19, 2022	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 499 of the SLC1A3 protein (p.Arg499Gln). This variant is present in population databases (rs138085358, gnomAD 0.01%). This missense change has been observed in individual(s) with ataxia (PMID: 25497598). This variant is also known as Arg454Gln. ClinVar contains an entry for this variant (Variation ID: 242994). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt SLC1A3 protein function. Studies have shown that this missense change alters SLC1A3 gene expression (PMID: 32741053). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 01, 2017	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Apr 14, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.29
Cadd	Uncertain	24
Dann	Benign	0.97
DEOGEN2	Benign	0.039	T;.;T;.
Eigen	Benign	-0.12
Eigen_PC	Benign	0.036
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.95	D;D;D;D
M_CAP	Benign	0.037	D
MetaRNN	Benign	0.28	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.65	T
Sift4G	Benign	0.22	T;T;T;T
Polyphen		0.38	.;.;B;.
Vest4		0.35
MVP		0.66
MPC		0.71
ClinPred		0.15	T
GERP RS		4.8
Varity_R		0.17
gMVP		0.87

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: rs138085358; hg19: chr5-36686238;