9-4576451-T-G

Variant names:

• chr9-4576451-T-G
• rs2072657
• NM_004170.6:c.999-118T>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004170.6(SLC1A1):​c.999-118T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.297 in 837,180 control chromosomes in the GnomAD database, including 37,810 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.28 (6081 hom., cov: 33)
  • Exomes 𝑓: 0.30 (31729 hom.)
• Consequence: SLC1A1 NM_004170.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.377
• Publications: 12 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 9-4576451-T-G is Benign according to our data. Variant chr9-4576451-T-G is described in ClinVar as Benign. ClinVar VariationId is 1231703.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.367 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC1A1	NM_004170.6	c.999-118T>G		intron_variant	Intron 9 of 11	ENST00000262352.8	NP_004161.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC1A1	ENST00000262352.8	c.999-118T>G		intron_variant	Intron 9 of 11	1	NM_004170.6	ENSP00000262352.3
SLC1A1	ENST00000422398.1	c.285-118T>G		intron_variant	Intron 3 of 4	4		ENSP00000414620.1
SPATA6L	ENST00000485616.5	n.*782-22063A>C		intron_variant	Intron 12 of 12	2		ENSP00000420003.1

Frequencies

GnomAD3 genomes AF: 0.280 AC: 42619 AN: 152036 Hom.: 6075 Cov.: 33

Gnomad AFR AF: 0.242

Gnomad AMI AF: 0.442

Gnomad AMR AF: 0.288

Gnomad ASJ AF: 0.264

Gnomad EAS AF: 0.296

Gnomad SAS AF: 0.380

Gnomad FIN AF: 0.226

Gnomad MID AF: 0.310

Gnomad NFE AF: 0.301

Gnomad OTH AF: 0.269

GnomAD4 exome AF: 0.301 AC: 206216 AN: 685026 Hom.: 31729 AF XY: 0.305 AC XY: 111348 AN XY: 364602

African (AFR) AF: 0.243 AC: 4417 AN: 18194

American (AMR) AF: 0.291 AC: 10286 AN: 35300

Ashkenazi Jewish (ASJ) AF: 0.257 AC: 5307 AN: 20656

East Asian (EAS) AF: 0.296 AC: 10233 AN: 34626

South Asian (SAS) AF: 0.371 AC: 24383 AN: 65708

European-Finnish (FIN) AF: 0.242 AC: 11914 AN: 49236

Middle Eastern (MID) AF: 0.295 AC: 1187 AN: 4028

European-Non Finnish (NFE) AF: 0.304 AC: 128369 AN: 422382

Other (OTH) AF: 0.290 AC: 10120 AN: 34896

GnomAD4 genome AF: 0.280 AC: 42648 AN: 152154 Hom.: 6081 Cov.: 33 AF XY: 0.279 AC XY: 20750 AN XY: 74400

African (AFR) AF: 0.242 AC: 10037 AN: 41492

American (AMR) AF: 0.288 AC: 4399 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.264 AC: 916 AN: 3468

East Asian (EAS) AF: 0.296 AC: 1533 AN: 5178

South Asian (SAS) AF: 0.381 AC: 1840 AN: 4826

European-Finnish (FIN) AF: 0.226 AC: 2400 AN: 10600

Middle Eastern (MID) AF: 0.316 AC: 93 AN: 294

European-Non Finnish (NFE) AF: 0.301 AC: 20457 AN: 67980

Other (OTH) AF: 0.270 AC: 570 AN: 2110

Alfa AF: 0.285 Hom.: 7419

Bravo AF: 0.279

Asia WGS AF: 0.330 AC: 1151 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Aug 20, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	3.4
DANN	Benign	0.48
PhyloP100		-0.38
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2072657; hg19: chr9-4576451; COSMIC: COSV52050745;