rs1554045196

Variant names:

• chr5-36676914-G-A
• rs1554045196
• NM_004172.5:c.590G>A

Variant summary

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

The NM_004172.5(SLC1A3):​c.590G>A​(p.Arg197Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,350 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: SLC1A3 NM_004172.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.49
• Publications: 0 publications found

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

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=0.08164975).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC1A3	NM_004172.5	c.590G>A	p.Arg197Lys	missense_variant	Exon 6 of 10	ENST00000265113.9	NP_004163.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC1A3	ENST00000265113.9	c.590G>A	p.Arg197Lys	missense_variant	Exon 6 of 10	1	NM_004172.5	ENSP00000265113.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461350 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 726962

African (AFR) AF: 0.00 AC: 0 AN: 33464

American (AMR) AF: 0.0000447 AC: 2 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39682

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86186

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53374

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111682

Other (OTH) AF: 0.00 AC: 0 AN: 60374

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

May 11, 2017

Athena Diagnostics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Uncertain:1

Mar 01, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with lysine, which is basic and polar, at codon 197 of the SLC1A3 protein (p.Arg197Lys). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with SLC1A3-related conditions. ClinVar contains an entry for this variant (Variation ID: 448408). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The lysine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	18
DANN	Benign	0.86
DEOGEN2	Benign	0.16	.;T;.
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.16
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.74	T;T;T
M_CAP	Benign	0.0079	T
MetaRNN	Benign	0.082	T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.4	.;L;L
PhyloP100		1.5
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-0.21	.;N;N
REVEL	Benign	0.084
Sift	Benign	1.0	.;T;T
Sift4G	Benign	0.91	T;T;T
Polyphen		0.0	.;B;.
Vest4		0.097
MutPred		0.50		.;Gain of disorder (P = 0.0443);Gain of disorder (P = 0.0443);
MVP		0.45
MPC		0.42
ClinPred		0.14	T
GERP RS		3.7
PromoterAI		-0.0035	Neutral
Varity_R		0.098
gMVP		0.76
Mutation Taster		=86/14	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: rs1554045196; hg19: chr5-36677016;