9-4544640-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_004170.6(SLC1A1):c.165T>C(p.Pro55=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00875 in 1,613,630 control chromosomes in the GnomAD database, including 77 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0063 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0090 (75 hom.)
• Consequence: SLC1A1 NM_004170.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.0110

Genes affected

SLC1A1 (HGNC:10939): (solute carrier family 1 member 1) This gene encodes a member of the high-affinity glutamate transporters that play an essential role in transporting glutamate across plasma membranes. In brain, these transporters are crucial in terminating the postsynaptic action of the neurotransmitter glutamate, and in maintaining extracellular glutamate concentrations below neurotoxic levels. This transporter also transports aspartate, and mutations in this gene are thought to cause dicarboxylicamino aciduria, also known as glutamate-aspartate transport defect. [provided by RefSeq, Mar 2010]

ACMG classification

Verdict is Benign. Variant got -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP6: Variant 9-4544640-T-C is Benign according to our data. Variant chr9-4544640-T-C is described in ClinVar as [Benign]. Clinvar id is 367039.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.011 with no splicing effect.
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC1A1	NM_004170.6	c.165T>C	p.Pro55=	synonymous_variant	2/12	ENST00000262352.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC1A1	ENST00000262352.8	c.165T>C	p.Pro55=	synonymous_variant	2/12	1	NM_004170.6	P1

Frequencies

GnomAD3 genomes AF: 0.00631 AC: 960 AN: 152236 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00186

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00635

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00517

Gnomad FIN AF: 0.000941

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0105

Gnomad OTH AF: 0.0100

GnomAD3 exomes AF: 0.00651 AC: 1636 AN: 251376 Hom.: 5 AF XY: 0.00657 AC XY: 892 AN XY: 135866

Gnomad AFR exome AF: 0.00203

Gnomad AMR exome AF: 0.00425

Gnomad ASJ exome AF: 0.00407

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00464

Gnomad FIN exome AF: 0.00227

Gnomad NFE exome AF: 0.0104

Gnomad OTH exome AF: 0.00750

GnomAD4 exome AF: 0.00901 AC: 13165 AN: 1461276 Hom.: 75 Cov.: 30 AF XY: 0.00901 AC XY: 6550 AN XY: 726960

Gnomad4 AFR exome AF: 0.00173

Gnomad4 AMR exome AF: 0.00483

Gnomad4 ASJ exome AF: 0.00394

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00439

Gnomad4 FIN exome AF: 0.00202

Gnomad4 NFE exome AF: 0.0106

Gnomad4 OTH exome AF: 0.00755

GnomAD4 genome AF: 0.00629 AC: 958 AN: 152354 Hom.: 2 Cov.: 32 AF XY: 0.00585 AC XY: 436 AN XY: 74492

Gnomad4 AFR AF: 0.00185

Gnomad4 AMR AF: 0.00634

Gnomad4 ASJ AF: 0.00259

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00497

Gnomad4 FIN AF: 0.000941

Gnomad4 NFE AF: 0.0105

Gnomad4 OTH AF: 0.00992

Alfa AF: 0.00834 Hom.: 3

Bravo AF: 0.00638

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.0107

EpiControl AF: 0.00883

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2023	SLC1A1: BP4, BP7, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 31, 2019	- -

Dicarboxylic aminoaciduria 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	-0.49
Cadd	Benign	7.5
Dann	Benign	0.78

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: rs142903137; hg19: chr9-4544640;