9-4564428-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_004170.6(SLC1A1):c.410G>A(p.Ser137Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000533 in 1,613,394 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00029 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000029 (0 hom.)
• Consequence: SLC1A1 NM_004170.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.18

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.057524443).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC1A1	NM_004170.6	c.410G>A	p.Ser137Asn	missense_variant	4/12	ENST00000262352.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC1A1	ENST00000262352.8	c.410G>A	p.Ser137Asn	missense_variant	4/12	1	NM_004170.6	P1
SLC1A1	ENST00000490167.1	n.454G>A		non_coding_transcript_exon_variant	3/3	3
SPATA6L	ENST00000485616.5	c.*782-10040C>T		intron_variant, NMD_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.000289 AC: 44 AN: 152266 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000989

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.0000439 AC: 11 AN: 250542 Hom.: 0 AF XY: 0.0000369 AC XY: 5 AN XY: 135368

Gnomad AFR exome AF: 0.000493

Gnomad AMR exome AF: 0.0000580

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000882

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000287 AC: 42 AN: 1461010 Hom.: 0 Cov.: 30 AF XY: 0.0000303 AC XY: 22 AN XY: 726784

Gnomad4 AFR exome AF: 0.000657

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000162

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.000289 AC: 44 AN: 152384 Hom.: 0 Cov.: 32 AF XY: 0.000268 AC XY: 20 AN XY: 74524

Gnomad4 AFR AF: 0.000986

Gnomad4 AMR AF: 0.0000653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.0000308 Hom.: 0

Bravo AF: 0.000238

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000741 AC: 9

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000594

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 10, 2022

The c.410G>A (p.S137N) alteration is located in exon 4 (coding exon 4) of the SLC1A1 gene. This alteration results from a G to A substitution at nucleotide position 410, causing the serine (S) at amino acid position 137 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.50
Cadd	Benign	20
Dann	Uncertain	0.99
DEOGEN2	Benign	0.31	T
Eigen	Benign	-0.13
Eigen_PC	Benign	0.015
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.76	T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.058	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.6	L
MutationTaster	Benign	0.82	D
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.070
Sift	Benign	0.080	T
Sift4G	Benign	0.19	T
Polyphen		0.037	B
Vest4		0.11
MVP		0.69
MPC		0.037
ClinPred		0.067	T
GERP RS		4.3
Varity_R		0.29
gMVP		0.54

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: rs149969951; hg19: chr9-4564428;