Genetic Variant SLC1A1:p.Ile90Ser (chr9-4561485-T-G) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_004170.6(SLC1A1):c.269T>G(p.Ile90Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,458,924 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I90T) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

SLC1A1
NM_004170.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 6.56

Publications

0 publications found

Variant links:

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]

SLC1A1 links:

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]

SPATA6L links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.964

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC1A1	NM_004170.6 link	c.269T>G	p.Ile90Ser	missense_variant	Exon 3 of 12	ENST00000262352.8	NP_004161.4	P43005

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SLC1A1	ENST00000262352.8 link	c.269T>G	p.Ile90Ser	missense_variant	Exon 3 of 12	1	NM_004170.6	ENSP00000262352.3	P43005
SLC1A1	ENST00000490167.1 link	n.313T>G		non_coding_transcript_exon_variant	Exon 2 of 3	3
SPATA6L	ENST00000485616.5 link	n.*782-7097A>C		intron_variant	Intron 12 of 12	2		ENSP00000420003.1	D3DRI0

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1458924

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726098

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33418

American (AMR)

AF:

0.00

AC:

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26116

East Asian (EAS)

AF:

0.00

AC:

AN:

39678

South Asian (SAS)

AF:

0.00

AC:

AN:

86182

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53406

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

9.01e-7

AC:

AN:

1109354

Other (OTH)

AF:

0.00

AC:

AN:

60290

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.91

BayesDel_addAF

Pathogenic

0.36

BayesDel_noAF

Pathogenic

0.28

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.79

Eigen

Pathogenic

0.83

Eigen_PC

Pathogenic

0.75

FATHMM_MKL

Uncertain

0.96

LIST_S2

Pathogenic

0.97

M_CAP

Uncertain

0.13

MetaRNN

Pathogenic

0.96

MetaSVM

Uncertain

0.26

MutationAssessor

Pathogenic

3.7

PhyloP100

6.6

PrimateAI

Uncertain

0.61

PROVEAN

Uncertain

-2.9

REVEL

Pathogenic

0.66

Sift

Uncertain

0.0010

Sift4G

Pathogenic

0.0010

Polyphen

1.0

Vest4

0.98

MutPred

0.81

Gain of disorder (P = 3e-04);

MVP

0.90

MPC

0.28

ClinPred

0.99

GERP RS

5.7

Varity_R

0.73

gMVP

0.96

Mutation Taster

=44/56

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over