9-4576680-T-C

Position:

• chr9-4576680-T-C

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.1110T>C​(p.Thr370Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.326 in 1,613,394 control chromosomes in the GnomAD database, including 91,370 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.38 (12023 hom., cov: 33)
  • Exomes 𝑓: 0.32 (79347 hom.)
• Consequence: SLC1A1 NM_004170.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -6.15

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=-0.89).
• BP6: Variant 9-4576680-T-C is Benign according to our data. Variant chr9-4576680-T-C is described in ClinVar as [Benign]. Clinvar id is 367052.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-6.15 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.581 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC1A1	NM_004170.6	c.1110T>C	p.Thr370Thr	synonymous_variant	10/12	ENST00000262352.8	NP_004161.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC1A1	ENST00000262352.8	c.1110T>C	p.Thr370Thr	synonymous_variant	10/12	1	NM_004170.6	ENSP00000262352.3
SLC1A1	ENST00000422398.1	c.396T>C	p.Thr132Thr	synonymous_variant	4/5	4		ENSP00000414620.1
SPATA6L	ENST00000485616.5	n.*782-22292A>G		intron_variant		2		ENSP00000420003.1

Frequencies

GnomAD3 genomes AF: 0.381 AC: 57950 AN: 151922 Hom.: 11979 Cov.: 33

Gnomad AFR AF: 0.509

Gnomad AMI AF: 0.227

Gnomad AMR AF: 0.354

Gnomad ASJ AF: 0.229

Gnomad EAS AF: 0.599

Gnomad SAS AF: 0.388

Gnomad FIN AF: 0.463

Gnomad MID AF: 0.185

Gnomad NFE AF: 0.293

Gnomad OTH AF: 0.335

GnomAD3 exomes AF: 0.363 AC: 91366 AN: 251418 Hom.: 17986 AF XY: 0.357 AC XY: 48444 AN XY: 135884

Gnomad AFR exome AF: 0.508

Gnomad AMR exome AF: 0.382

Gnomad ASJ exome AF: 0.222

Gnomad EAS exome AF: 0.610

Gnomad SAS exome AF: 0.372

Gnomad FIN exome AF: 0.456

Gnomad NFE exome AF: 0.292

Gnomad OTH exome AF: 0.329

GnomAD4 exome AF: 0.321 AC: 468653 AN: 1461354 Hom.: 79347 Cov.: 39 AF XY: 0.320 AC XY: 232990 AN XY: 726974

Gnomad4 AFR exome AF: 0.506

Gnomad4 AMR exome AF: 0.380

Gnomad4 ASJ exome AF: 0.222

Gnomad4 EAS exome AF: 0.605

Gnomad4 SAS exome AF: 0.365

Gnomad4 FIN exome AF: 0.454

Gnomad4 NFE exome AF: 0.295

Gnomad4 OTH exome AF: 0.325

GnomAD4 genome AF: 0.382 AC: 58042 AN: 152040 Hom.: 12023 Cov.: 33 AF XY: 0.388 AC XY: 28831 AN XY: 74318

Gnomad4 AFR AF: 0.510

Gnomad4 AMR AF: 0.354

Gnomad4 ASJ AF: 0.229

Gnomad4 EAS AF: 0.599

Gnomad4 SAS AF: 0.387

Gnomad4 FIN AF: 0.463

Gnomad4 NFE AF: 0.293

Gnomad4 OTH AF: 0.338

Alfa AF: 0.308 Hom.: 19235

Bravo AF: 0.381

Asia WGS AF: 0.505 AC: 1757 AN: 3478

EpiCase AF: 0.277

EpiControl AF: 0.273

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	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	- -

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	-0.89
CADD	Benign	0.0050
DANN	Benign	0.37

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: rs301430; hg19: chr9-4576680; COSMIC: COSV52051461;