5-36608492-T-A

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_004172.5(SLC1A3):c.69T>A(p.Arg23=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00211 in 1,614,020 control chromosomes in the GnomAD database, including 31 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0032 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0020 (29 hom.)
• Consequence: SLC1A3 NM_004172.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -2.12

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]

ACMG classification

Verdict is Benign. Variant got -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 5-36608492-T-A is Benign according to our data. Variant chr5-36608492-T-A is described in ClinVar as [Likely_benign]. Clinvar id is 791028.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.12 with no splicing effect.
• BS2: High AC in GnomAd at 482 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC1A3	NM_004172.5	c.69T>A	p.Arg23=	synonymous_variant	2/10	ENST00000265113.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC1A3	ENST00000265113.9	c.69T>A	p.Arg23=	synonymous_variant	2/10	1	NM_004172.5	P1

Frequencies

GnomAD3 genomes AF: 0.00317 AC: 482 AN: 152170 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0272

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00244

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00336 AC: 844 AN: 251398 Hom.: 8 AF XY: 0.00325 AC XY: 441 AN XY: 135872

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.000202

Gnomad ASJ exome AF: 0.000198

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0266

Gnomad NFE exome AF: 0.00208

Gnomad OTH exome AF: 0.00326

GnomAD4 exome AF: 0.00200 AC: 2930 AN: 1461732 Hom.: 29 Cov.: 31 AF XY: 0.00205 AC XY: 1493 AN XY: 727186

Gnomad4 AFR exome AF: 0.0000598

Gnomad4 AMR exome AF: 0.000313

Gnomad4 ASJ exome AF: 0.000191

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.0279

Gnomad4 NFE exome AF: 0.00117

Gnomad4 OTH exome AF: 0.00185

GnomAD4 genome AF: 0.00317 AC: 482 AN: 152288 Hom.: 2 Cov.: 32 AF XY: 0.00436 AC XY: 325 AN XY: 74464

Gnomad4 AFR AF: 0.000217

Gnomad4 AMR AF: 0.000588

Gnomad4 ASJ AF: 0.000864

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0272

Gnomad4 NFE AF: 0.00244

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00191 Hom.: 1

Bravo AF: 0.000790

EpiCase AF: 0.00136

EpiControl AF: 0.000711

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	Invitae	Jan 21, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	SLC1A3: BP4, BP7, BS2 -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Apr 13, 2021

- -

Episodic ataxia type 6 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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
BayesDel_noAF	Benign	-0.83
Cadd	Benign	2.1
Dann	Benign	0.73

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: rs140080134; hg19: chr5-36608594;