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GeneBe

rs1553689859

chr3-11026351-C-Achr3-11026351-C-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1PM5PP2PP3_StrongPP5_Moderate

The NM_003042.4(SLC6A1):c.1070C>A(p.Ala357Glu) variant causes a missense change involving the alteration of a conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A357V) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

SLC6A1
NM_003042.4 missense

Scores

10
3
1

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 7.65
Variant links:
Genes affected
SLC6A1 (HGNC:11042): (solute carrier family 6 member 1) The protein encoded by this gene is a gamma-aminobutyric acid (GABA) transporter that localizes to the plasma membrane. The encoded protein removes GABA from the synaptic cleft, restoring it to presynaptic terminals. [provided by RefSeq, Jan 2017]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 ACMG points.

PM1
?
    PM1 - Located in a mutational hot spot and/or critical and well-established functional domain (e.g., active site of an enzyme) without benign variation
In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 6 uncertain in NM_003042.4
PM5
?
    PM5 - Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before
Other missense variant is known to change same aminoacid residue: Variant chr3-11026351-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 542198.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
PP2
?
    PP2 - Missense variant in a gene that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease
Missense variant where missense usually causes diseases, SLC6A1
PP3
?
    PP3 - Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.)
MetaRNN computational evidence supports a deleterious effect, 0.973
PP5
?
    PP5 - Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 3-11026351-C-A is Pathogenic according to our data. Variant chr3-11026351-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1299344.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
SLC6A1NM_003042.4 linkuse as main transcriptc.1070C>A p.Ala357Glu missense_variant 10/16 ENST00000287766.10

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
SLC6A1ENST00000287766.10 linkuse as main transcriptc.1070C>A p.Ala357Glu missense_variant 10/161 NM_003042.4 P1

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
Cov.:
32
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
0.00
AC:
0
AN:
1461270
Hom.:
0
Cov.:
33
AF XY:
0.00
AC XY:
0
AN XY:
726928
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
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:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
Cov.:
32

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Myoclonic-astatic epilepsy Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingInstitute of Human Genetics, University of Leipzig Medical CenterOct 01, 2021- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.98
BayesDel_addAF
Pathogenic
0.41
D
BayesDel_noAF
Pathogenic
0.35
Cadd
Pathogenic
31
Dann
Uncertain
1.0
DEOGEN2
Uncertain
0.55
D;D;D;D;D;.;D;.;D;D;D;D;.;D;D;D;.;D;D;D;.;D;D;D;.;.
Eigen
Pathogenic
1.0
Eigen_PC
Pathogenic
0.93
FATHMM_MKL
Pathogenic
0.99
D
M_CAP
Pathogenic
0.69
D
MetaRNN
Pathogenic
0.97
D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Uncertain
0.70
D
MutationAssessor
Pathogenic
3.7
H;H;H;H;H;.;H;.;H;H;H;H;.;H;H;H;.;H;H;H;.;H;H;H;.;.
MutationTaster
Benign
1.0
D;D
PrimateAI
Pathogenic
0.87
D
Polyphen
1.0
D;D;D;D;D;.;D;.;D;D;D;D;.;D;D;D;.;D;D;D;.;D;D;D;.;.
Vest4
0.90
MutPred
0.85
Gain of disorder (P = 0.0266);Gain of disorder (P = 0.0266);Gain of disorder (P = 0.0266);Gain of disorder (P = 0.0266);Gain of disorder (P = 0.0266);.;Gain of disorder (P = 0.0266);.;Gain of disorder (P = 0.0266);Gain of disorder (P = 0.0266);Gain of disorder (P = 0.0266);Gain of disorder (P = 0.0266);.;Gain of disorder (P = 0.0266);Gain of disorder (P = 0.0266);Gain of disorder (P = 0.0266);.;Gain of disorder (P = 0.0266);Gain of disorder (P = 0.0266);Gain of disorder (P = 0.0266);.;Gain of disorder (P = 0.0266);Gain of disorder (P = 0.0266);Gain of disorder (P = 0.0266);Gain of disorder (P = 0.0266);Gain of disorder (P = 0.0266);
MVP
0.95
MPC
2.3
ClinPred
1.0
D
GERP RS
5.5
Varity_R
0.97
gMVP
0.97

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-11068037; API