9-4544624-T-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004170.6(SLC1A1):c.149T>A(p.Phe50Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.00333 in 1,613,686 control chromosomes in the GnomAD database, including 151 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.017 (82 hom., cov: 32)
  • Exomes 𝑓: 0.0019 (69 hom.)
• Consequence: SLC1A1 NM_004170.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 4.75

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008016139).
• BP6: Variant 9-4544624-T-A is Benign according to our data. Variant chr9-4544624-T-A is described in ClinVar as [Benign]. Clinvar id is 367038.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0567 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC1A1	NM_004170.6	c.149T>A	p.Phe50Tyr	missense_variant	2/12	ENST00000262352.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC1A1	ENST00000262352.8	c.149T>A	p.Phe50Tyr	missense_variant	2/12	1	NM_004170.6	P1

Frequencies

GnomAD3 genomes AF: 0.0170 AC: 2591 AN: 152198 Hom.: 81 Cov.: 32

Gnomad AFR AF: 0.0586

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00766

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: 0.000176

Gnomad OTH AF: 0.0148

GnomAD3 exomes AF: 0.00450 AC: 1131 AN: 251378 Hom.: 26 AF XY: 0.00330 AC XY: 448 AN XY: 135862

Gnomad AFR exome AF: 0.0595

Gnomad AMR exome AF: 0.00350

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000261

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000132

Gnomad OTH exome AF: 0.00310

GnomAD4 exome AF: 0.00190 AC: 2774 AN: 1461370 Hom.: 69 Cov.: 30 AF XY: 0.00162 AC XY: 1181 AN XY: 727032

Gnomad4 AFR exome AF: 0.0622

Gnomad4 AMR exome AF: 0.00427

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000267

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000172

Gnomad4 OTH exome AF: 0.00441

GnomAD4 genome AF: 0.0171 AC: 2597 AN: 152316 Hom.: 82 Cov.: 32 AF XY: 0.0167 AC XY: 1240 AN XY: 74474

Gnomad4 AFR AF: 0.0586

Gnomad4 AMR AF: 0.00765

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000176

Gnomad4 OTH AF: 0.0147

Alfa AF: 0.00242 Hom.: 5

Bravo AF: 0.0200

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0556 AC: 245

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.00558 AC: 677

Asia WGS AF: 0.00433 AC: 15 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Dicarboxylic aminoaciduria 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. -

SLC1A1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 11, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.057
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.40
Cadd	Benign	18
Dann	Benign	0.96
DEOGEN2	Benign	0.14	T
Eigen	Benign	-0.15
Eigen_PC	Benign	0.081
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.67	T
MetaRNN	Benign	0.0080	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.65	N
MutationTaster	Benign	0.73	D
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-0.47	N
REVEL	Benign	0.067
Sift	Benign	0.23	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.50
MVP		0.31
MPC		0.036
ClinPred		0.014	T
GERP RS		5.5
Varity_R		0.37
gMVP		0.52

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: rs2228621; hg19: chr9-4544624;