rs115702388

chr5-36680454-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_004172.5(SLC1A3):c.1154G>A(p.Arg385His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000146 in 1,614,182 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. R385R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00056 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00010 (0 hom.)
• Consequence: SLC1A3 NM_004172.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 8.18

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 Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.035968542).
• BP6: Variant 5-36680454-G-A is Benign according to our data. Variant chr5-36680454-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 353321.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd at 85 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC1A3	NM_004172.5	c.1154G>A	p.Arg385His	missense_variant	8/10	ENST00000265113.9
SLC1A3-AS1	XR_007058736.1	n.76-11743C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC1A3	ENST00000265113.9	c.1154G>A	p.Arg385His	missense_variant	8/10	1	NM_004172.5	P1
SLC1A3-AS1	ENST00000510740.1	n.61-11743C>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.000559 AC: 85 AN: 152182 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00186

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000195 AC: 49 AN: 251386 Hom.: 0 AF XY: 0.000162 AC XY: 22 AN XY: 135872

Gnomad AFR exome AF: 0.00215

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000704

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000103 AC: 151 AN: 1461882 Hom.: 0 Cov.: 32 AF XY: 0.000113 AC XY: 82 AN XY: 727244

Gnomad4 AFR exome AF: 0.00173

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000612

Gnomad4 OTH exome AF: 0.000248

GnomAD4 genome AF: 0.000558 AC: 85 AN: 152300 Hom.: 1 Cov.: 32 AF XY: 0.000497 AC XY: 37 AN XY: 74478

Gnomad4 AFR AF: 0.00185

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000146 Hom.: 0

Bravo AF: 0.000593

ESP6500AA AF: 0.00250 AC: 11

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000239 AC: 29

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 14, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 08, 2024	- -

Spastic ataxia Benign:1

Benign, criteria provided, single submitter

research

Molecular Medicine for Neurodegenerative and Neuromuscular Diseases Unit, IRCCS Fondazione Stella Maris

Jul 12, 2021

- -

Episodic ataxia type 6 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.75
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Uncertain	0.0
Cadd	Pathogenic	33
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.11	T;.;D;.
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	D;D;D;D
M_CAP	Benign	0.045	D
MetaRNN	Benign	0.036	T;T;T;T
MetaSVM	Uncertain	-0.26	T
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.79	T
Sift4G	Uncertain	0.056	T;D;T;D
Polyphen		1.0	.;.;D;.
Vest4		0.60
MVP		0.76
MPC		1.4
ClinPred		0.15	T
GERP RS		5.8
Varity_R		0.64
gMVP		0.77

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: rs115702388; hg19: chr5-36680556; COSMIC: COSV99468078; COSMIC: COSV99468078;