Genetic Variant SLC1A3:p.Glu229Gln (chr5-36677009-G-C) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_004172.5(SLC1A3):c.685G>C(p.Glu229Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,816 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. E229K) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

SLC1A3
NM_004172.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.77

Publications

0 publications found

Variant links:

Genes affected

SLC1A3 (HGNC:10941): (solute carrier family 1 member 3) This gene encodes a member of a member of a high affinity glutamate transporter family. This gene functions in the termination of excitatory neurotransmission in central nervous system. Mutations are associated with episodic ataxia, Type 6. Alternative splicing results in multiple transcript variants.[provided by RefSeq, Feb 2014]

SLC1A3 links:

SLC1A3-AS1 (HGNC:56374): (SLC1A3 antisense RNA 1)

SLC1A3-AS1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.888

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004172.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SLC1A3	NM_004172.5	MANE Select	c.685G>C	p.Glu229Gln	missense	Exon 6 of 10	NP_004163.3
SLC1A3	NM_001438458.1		c.685G>C	p.Glu229Gln	missense	Exon 6 of 11	NP_001425387.1
SLC1A3	NM_001438454.1		c.685G>C	p.Glu229Gln	missense	Exon 7 of 11	NP_001425383.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SLC1A3	ENST00000265113.9	TSL:1 MANE Select	c.685G>C	p.Glu229Gln	missense	Exon 6 of 10	ENSP00000265113.4	P43003-1
SLC1A3	ENST00000381918.4	TSL:1	c.685G>C	p.Glu229Gln	missense	Exon 6 of 10	ENSP00000371343.4	P43003-1
SLC1A3	ENST00000680232.1		c.685G>C	p.Glu229Gln	missense	Exon 6 of 11	ENSP00000506207.1	A0A7P0TAG7

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461816

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727216

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.00

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53412

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111956

Other (OTH)

AF:

0.00

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Uncertain

0.045

BayesDel_noAF

Benign

-0.17

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.28

Eigen

Benign

0.15

Eigen_PC

Uncertain

0.29

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Benign

0.84

M_CAP

Benign

0.013

MetaRNN

Pathogenic

0.89

MetaSVM

Benign

-0.93

MutationAssessor

Benign

1.3

PhyloP100

7.8

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-0.76

REVEL

Benign

0.21

Sift

Benign

0.17

Sift4G

Benign

0.26

Polyphen

0.019

Vest4

0.70

MutPred

0.82

Gain of helix (P = 0.1736)

MVP

0.69

MPC

1.2

ClinPred

0.87

GERP RS

5.9

PromoterAI

-0.0030

Neutral

(source)

Varity_R

0.25

gMVP

0.72

Mutation Taster

=71/29

polymorphism

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over