9-4574022-A-C

Variant names:

• chr9-4574022-A-C
• rs12682807
• NM_004170.6:c.875+8A>C

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.875+8A>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.107 in 1,565,798 control chromosomes in the GnomAD database, including 10,104 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.086 (833 hom., cov: 32)
  • Exomes 𝑓: 0.11 (9271 hom.)
• Consequence: SLC1A1 NM_004170.6 splice_region, intron
• Scores: Splicing: ADA: 0.00002237
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.832
• 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=-0.78).
• BP6: Variant 9-4574022-A-C is Benign according to our data. Variant chr9-4574022-A-C is described in ClinVar as Benign. ClinVar VariationId is 367049.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.234 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC1A1	NM_004170.6	MANE Select	c.875+8A>C		splice_region intron	N/A	NP_004161.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC1A1	ENST00000262352.8	TSL:1 MANE Select	c.875+8A>C		splice_region intron	N/A	ENSP00000262352.3	P43005
	SLC1A1	ENST00000931882.1		c.767+1634A>C		intron	N/A	ENSP00000601941.1
	SLC1A1	ENST00000954075.1		c.734+8A>C		splice_region intron	N/A	ENSP00000624134.1

Frequencies

GnomAD3 genomes AF: 0.0862 AC: 13122 AN: 152164 Hom.: 832 Cov.: 32

Gnomad AFR AF: 0.0210

Gnomad AMI AF: 0.133

Gnomad AMR AF: 0.0859

Gnomad ASJ AF: 0.0343

Gnomad EAS AF: 0.245

Gnomad SAS AF: 0.0707

Gnomad FIN AF: 0.147

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.108

Gnomad OTH AF: 0.0793

GnomAD2 exomes AF: 0.106 AC: 26578 AN: 251340 AF XY: 0.102

Gnomad AFR exome AF: 0.0194

Gnomad AMR exome AF: 0.106

Gnomad ASJ exome AF: 0.0348

Gnomad EAS exome AF: 0.250

Gnomad FIN exome AF: 0.144

Gnomad NFE exome AF: 0.105

Gnomad OTH exome AF: 0.0951

GnomAD4 exome AF: 0.109 AC: 154736 AN: 1413516 Hom.: 9271 Cov.: 23 AF XY: 0.107 AC XY: 75779 AN XY: 706132

African (AFR) AF: 0.0168 AC: 546 AN: 32422

American (AMR) AF: 0.103 AC: 4582 AN: 44658

Ashkenazi Jewish (ASJ) AF: 0.0363 AC: 938 AN: 25870

East Asian (EAS) AF: 0.193 AC: 7610 AN: 39462

South Asian (SAS) AF: 0.0641 AC: 5467 AN: 85336

European-Finnish (FIN) AF: 0.145 AC: 7752 AN: 53332

Middle Eastern (MID) AF: 0.0215 AC: 122 AN: 5662

European-Non Finnish (NFE) AF: 0.114 AC: 121891 AN: 1068058

Other (OTH) AF: 0.0993 AC: 5828 AN: 58716

GnomAD4 genome AF: 0.0862 AC: 13121 AN: 152282 Hom.: 833 Cov.: 32 AF XY: 0.0879 AC XY: 6546 AN XY: 74474

African (AFR) AF: 0.0210 AC: 872 AN: 41566

American (AMR) AF: 0.0860 AC: 1316 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0343 AC: 119 AN: 3472

East Asian (EAS) AF: 0.245 AC: 1271 AN: 5180

South Asian (SAS) AF: 0.0706 AC: 341 AN: 4830

European-Finnish (FIN) AF: 0.147 AC: 1563 AN: 10610

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.108 AC: 7346 AN: 68014

Other (OTH) AF: 0.0790 AC: 167 AN: 2114

Alfa AF: 0.0893 Hom.: 889

Bravo AF: 0.0808

Asia WGS AF: 0.142 AC: 494 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Dicarboxylic aminoaciduria (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	4.9
DANN	Benign	0.72
PhyloP100		0.83
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000022
dbscSNV1_RF	Benign	0.0
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: rs12682807; hg19: chr9-4574022; COSMIC: COSV104387544;