rs2228622

Positions:

• chr9-4564432-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_004170.6(SLC1A1):​c.414G>A​(p.Thr138=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.402 in 1,610,108 control chromosomes in the GnomAD database, including 133,243 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.35 (10256 hom., cov: 33)
  • Exomes 𝑓: 0.41 (122987 hom.)
• Consequence: SLC1A1 NM_004170.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.901

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]

SPATA6L (HGNC:25472): (spermatogenesis associated 6 like) Predicted to enable myosin light chain binding activity. Predicted to be involved in spermatogenesis. Predicted to be located in sperm connecting piece. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant 9-4564432-G-A is Benign according to our data. Variant chr9-4564432-G-A is described in ClinVar as [Benign]. Clinvar id is 367042.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-4564432-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.901 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.436 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC1A1	NM_004170.6	c.414G>A	p.Thr138=	synonymous_variant	4/12	ENST00000262352.8	NP_004161.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC1A1	ENST00000262352.8	c.414G>A	p.Thr138=	synonymous_variant	4/12	1	NM_004170.6	ENSP00000262352	P1
SLC1A1	ENST00000490167.1	n.458G>A		non_coding_transcript_exon_variant	3/3	3
SPATA6L	ENST00000485616.5	c.*782-10044C>T		intron_variant, NMD_transcript_variant		2		ENSP00000420003

Frequencies

GnomAD3 genomes AF: 0.354 AC: 53845 AN: 152010 Hom.: 10263 Cov.: 33

Gnomad AFR AF: 0.218

Gnomad AMI AF: 0.365

Gnomad AMR AF: 0.414

Gnomad ASJ AF: 0.510

Gnomad EAS AF: 0.251

Gnomad SAS AF: 0.452

Gnomad FIN AF: 0.340

Gnomad MID AF: 0.491

Gnomad NFE AF: 0.417

Gnomad OTH AF: 0.397

GnomAD3 exomes AF: 0.392 AC: 97515 AN: 248952 Hom.: 19798 AF XY: 0.401 AC XY: 53891 AN XY: 134472

Gnomad AFR exome AF: 0.210

Gnomad AMR exome AF: 0.407

Gnomad ASJ exome AF: 0.517

Gnomad EAS exome AF: 0.246

Gnomad SAS exome AF: 0.452

Gnomad FIN exome AF: 0.340

Gnomad NFE exome AF: 0.418

Gnomad OTH exome AF: 0.425

GnomAD4 exome AF: 0.407 AC: 593659 AN: 1457980 Hom.: 122987 Cov.: 33 AF XY: 0.410 AC XY: 297751 AN XY: 725346

Gnomad4 AFR exome AF: 0.215

Gnomad4 AMR exome AF: 0.410

Gnomad4 ASJ exome AF: 0.521

Gnomad4 EAS exome AF: 0.263

Gnomad4 SAS exome AF: 0.454

Gnomad4 FIN exome AF: 0.333

Gnomad4 NFE exome AF: 0.414

Gnomad4 OTH exome AF: 0.413

GnomAD4 genome AF: 0.354 AC: 53859 AN: 152128 Hom.: 10256 Cov.: 33 AF XY: 0.355 AC XY: 26374 AN XY: 74352

Gnomad4 AFR AF: 0.217

Gnomad4 AMR AF: 0.414

Gnomad4 ASJ AF: 0.510

Gnomad4 EAS AF: 0.251

Gnomad4 SAS AF: 0.452

Gnomad4 FIN AF: 0.340

Gnomad4 NFE AF: 0.417

Gnomad4 OTH AF: 0.397

Alfa AF: 0.418 Hom.: 23299

Bravo AF: 0.353

Asia WGS AF: 0.362 AC: 1256 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Dicarboxylic aminoaciduria Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
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. -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 18, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	0.86
DANN	Benign	0.83

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2228622; hg19: chr9-4564432; COSMIC: COSV52058356;