9-4490760-G-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Moderate BP6_Moderate BP7 BS1 BS2

The NM_004170.6(SLC1A1):c.81G>C(p.Ala27=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0232 in 1,611,722 control chromosomes in the GnomAD database, including 534 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Synonymous variant affecting the same amino acid position (i.e. A27A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.016 (35 hom., cov: 34)
  • Exomes 𝑓: 0.024 (499 hom.)
• Consequence: SLC1A1 NM_004170.6 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.70

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.33).
• BP6: Variant 9-4490760-G-C is Benign according to our data. Variant chr9-4490760-G-C is described in ClinVar as [Benign]. Clinvar id is 367033.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-1.7 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0163 (2481/152290) while in subpopulation NFE AF= 0.0264 (1794/68002). AF 95% confidence interval is 0.0254. There are 35 homozygotes in gnomad4. There are 1128 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 35 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC1A1	NM_004170.6	c.81G>C	p.Ala27=	synonymous_variant	1/12	ENST00000262352.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC1A1	ENST00000262352.8	c.81G>C	p.Ala27=	synonymous_variant	1/12	1	NM_004170.6	P1

Frequencies

GnomAD3 genomes AF: 0.0163 AC: 2481 AN: 152174 Hom.: 35 Cov.: 34

Gnomad AFR AF: 0.00533

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.00766

Gnomad ASJ AF: 0.00720

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00559

Gnomad FIN AF: 0.0256

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0264

Gnomad OTH AF: 0.0105

GnomAD3 exomes AF: 0.0157 AC: 3856 AN: 245466 Hom.: 59 AF XY: 0.0157 AC XY: 2097 AN XY: 133552

Gnomad AFR exome AF: 0.00439

Gnomad AMR exome AF: 0.00666

Gnomad ASJ exome AF: 0.00281

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00637

Gnomad FIN exome AF: 0.0272

Gnomad NFE exome AF: 0.0244

Gnomad OTH exome AF: 0.0150

GnomAD4 exome AF: 0.0239 AC: 34924 AN: 1459432 Hom.: 499 Cov.: 30 AF XY: 0.0233 AC XY: 16887 AN XY: 726128

Gnomad4 AFR exome AF: 0.00372

Gnomad4 AMR exome AF: 0.00701

Gnomad4 ASJ exome AF: 0.00392

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00669

Gnomad4 FIN exome AF: 0.0255

Gnomad4 NFE exome AF: 0.0281

Gnomad4 OTH exome AF: 0.0200

GnomAD4 genome AF: 0.0163 AC: 2481 AN: 152290 Hom.: 35 Cov.: 34 AF XY: 0.0151 AC XY: 1128 AN XY: 74468

Gnomad4 AFR AF: 0.00532

Gnomad4 AMR AF: 0.00765

Gnomad4 ASJ AF: 0.00720

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00559

Gnomad4 FIN AF: 0.0256

Gnomad4 NFE AF: 0.0264

Gnomad4 OTH AF: 0.0104

Alfa AF: 0.0111 Hom.: 5

Bravo AF: 0.0146

Asia WGS AF: 0.00202 AC: 8 AN: 3474

EpiCase AF: 0.0255

EpiControl AF: 0.0231

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.33
Cadd	Benign	9.1
Dann	Benign	0.93

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: rs2229885; hg19: chr9-4490760; COSMIC: COSV52055903;