5-36608438-T-C

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.15T>C(p.Asn5=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000729 in 1,613,780 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00062 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00074 (2 hom.)
• Consequence: SLC1A3 NM_004172.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.0520

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=-0.65).
• BP6: Variant 5-36608438-T-C is Benign according to our data. Variant chr5-36608438-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 353306.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-36608438-T-C is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.052 with no splicing effect.
• BS2: High AC in GnomAd at 95 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC1A3	NM_004172.5	c.15T>C	p.Asn5=	synonymous_variant	2/10	ENST00000265113.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC1A3	ENST00000265113.9	c.15T>C	p.Asn5=	synonymous_variant	2/10	1	NM_004172.5	P1

Frequencies

GnomAD3 genomes AF: 0.000625 AC: 95 AN: 151964 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00125

Gnomad FIN AF: 0.000662

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00106

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000573 AC: 144 AN: 251244 Hom.: 0 AF XY: 0.000685 AC XY: 93 AN XY: 135790

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000751

Gnomad FIN exome AF: 0.00116

Gnomad NFE exome AF: 0.000748

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.000740 AC: 1081 AN: 1461698 Hom.: 2 Cov.: 31 AF XY: 0.000754 AC XY: 548 AN XY: 727144

Gnomad4 AFR exome AF: 0.0000598

Gnomad4 AMR exome AF: 0.0000895

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000765

Gnomad4 FIN exome AF: 0.000637

Gnomad4 NFE exome AF: 0.000833

Gnomad4 OTH exome AF: 0.000712

GnomAD4 genome AF: 0.000625 AC: 95 AN: 152082 Hom.: 0 Cov.: 32 AF XY: 0.000632 AC XY: 47 AN XY: 74356

Gnomad4 AFR AF: 0.000145

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00125

Gnomad4 FIN AF: 0.000662

Gnomad4 NFE AF: 0.00106

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000503 Hom.: 0

Bravo AF: 0.000400

EpiCase AF: 0.000927

EpiControl AF: 0.000533

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Nov 27, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	SLC1A3: BP4, BP7 -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Feb 22, 2017

- -

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
BayesDel_noAF	Benign	-0.65
Cadd	Benign	6.7
Dann	Benign	0.64

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: rs143791614; hg19: chr5-36608540;