rs2228622

Variant names:

• chr9-4564432-G-A
• rs2228622
• NM_004170.6:c.414G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_004170.6(SLC1A1):​c.414G>A​(p.Thr138Thr) 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
• Publications: 46 publications found

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

Our verdict: Benign. The variant received -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 VariationId is 367042.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004170.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC1A1	NM_004170.6	MANE Select	c.414G>A	p.Thr138Thr	synonymous	Exon 4 of 12	NP_004161.4

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC1A1	ENST00000262352.8	TSL:1 MANE Select	c.414G>A	p.Thr138Thr	synonymous	Exon 4 of 12	ENSP00000262352.3
	SLC1A1	ENST00000490167.1	TSL:3	n.458G>A		non_coding_transcript_exon	Exon 3 of 3
	SPATA6L	ENST00000485616.5	TSL:2	n.*782-10044C>T		intron	N/A	ENSP00000420003.1

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

GnomAD2 exomes AF: 0.392 AC: 97515 AN: 248952 AF XY: 0.401

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 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

African (AFR) AF: 0.215 AC: 7193 AN: 33440

American (AMR) AF: 0.410 AC: 18251 AN: 44484

Ashkenazi Jewish (ASJ) AF: 0.521 AC: 13577 AN: 26078

East Asian (EAS) AF: 0.263 AC: 10410 AN: 39642

South Asian (SAS) AF: 0.454 AC: 38999 AN: 85908

European-Finnish (FIN) AF: 0.333 AC: 17767 AN: 53290

Middle Eastern (MID) AF: 0.519 AC: 2987 AN: 5750

European-Non Finnish (NFE) AF: 0.414 AC: 459574 AN: 1109106

Other (OTH) AF: 0.413 AC: 24901 AN: 60282

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

African (AFR) AF: 0.217 AC: 9022 AN: 41504

American (AMR) AF: 0.414 AC: 6334 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.510 AC: 1771 AN: 3470

East Asian (EAS) AF: 0.251 AC: 1302 AN: 5180

South Asian (SAS) AF: 0.452 AC: 2179 AN: 4824

European-Finnish (FIN) AF: 0.340 AC: 3599 AN: 10580

Middle Eastern (MID) AF: 0.483 AC: 142 AN: 294

European-Non Finnish (NFE) AF: 0.417 AC: 28339 AN: 67968

Other (OTH) AF: 0.397 AC: 839 AN: 2112

Alfa AF: 0.401 Hom.: 45343

Bravo AF: 0.353

Asia WGS AF: 0.362 AC: 1256 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Dicarboxylic aminoaciduria (2)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	0.86
DANN	Benign	0.83
PhyloP100		-0.90
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2228622; hg19: chr9-4564432; COSMIC: COSV52058356;