chr3-11020276-A-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 3P and 12B. PM2PP2BP4_StrongBP6_Very_Strong

The ENST00000287766.10(SLC6A1):​c.535A>T​(p.Met179Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,148 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M179V) has been classified as Benign.

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

SLC6A1
ENST00000287766.10 missense

Scores

19

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.0710
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 Benign. Variant got -9 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), SLC6A1. . Gene score misZ 4.1766 (greater than the threshold 3.09). Trascript score misZ 4.9229 (greater than threshold 3.09). GenCC has associacion of gene with myoclonic-atonic epilepsy, myoclonic-astatic epilepsy.
BP4
Computational evidence support a benign effect (MetaRNN=0.058456093).
BP6
Variant 3-11020276-A-T is Benign according to our data. Variant chr3-11020276-A-T is described in ClinVar as [Likely_benign]. Clinvar id is 1054920.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
SLC6A1NM_003042.4 linkuse as main transcriptc.535A>T p.Met179Leu missense_variant 6/16 ENST00000287766.10 NP_003033.3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
SLC6A1ENST00000287766.10 linkuse as main transcriptc.535A>T p.Met179Leu missense_variant 6/161 NM_003042.4 ENSP00000287766 P1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD3 exomes
AF:
0.00000400
AC:
1
AN:
250100
Hom.:
0
AF XY:
0.00000740
AC XY:
1
AN XY:
135128
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
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:
6.84e-7
AC:
1
AN:
1461148
Hom.:
0
Cov.:
30
AF XY:
0.00
AC XY:
0
AN XY:
726762
show subpopulations
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:
8.99e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Inborn genetic diseases Benign:1
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsMar 23, 2024This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Myoclonic-atonic epilepsy Benign:1
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpOct 13, 2023- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.067
BayesDel_addAF
Benign
-0.26
T
BayesDel_noAF
Benign
-0.61
CADD
Benign
0.12
DANN
Benign
0.80
DEOGEN2
Benign
0.087
T;T;T;.;T;T;.;T;.;T;T;T;T;.;T;T;T;.;T;T;T;.;T;T;T;.;.
Eigen
Benign
-1.6
Eigen_PC
Benign
-1.5
FATHMM_MKL
Benign
0.15
N
LIST_S2
Benign
0.20
.;.;.;T;.;.;.;.;.;.;.;.;.;D;.;.;.;T;.;.;.;T;.;.;T;T;T
M_CAP
Benign
0.0083
T
MetaRNN
Benign
0.028
T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM
Benign
-0.97
T
MutationAssessor
Benign
-0.81
N;N;N;.;N;N;.;N;.;N;N;N;N;.;N;N;N;.;N;N;N;.;N;N;N;.;.
MutationTaster
Benign
0.56
D;N
PrimateAI
Benign
0.23
T
PROVEAN
Benign
0.090
.;N;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
REVEL
Benign
0.079
Sift
Benign
1.0
.;T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G
Benign
1.0
.;T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Polyphen
0.0
B;B;B;.;B;B;.;B;.;B;B;B;B;.;B;B;B;.;B;B;B;.;B;B;B;.;.
Vest4
0.12
MutPred
0.36
Loss of disorder (P = 0.1935);Loss of disorder (P = 0.1935);Loss of disorder (P = 0.1935);.;Loss of disorder (P = 0.1935);Loss of disorder (P = 0.1935);.;Loss of disorder (P = 0.1935);.;Loss of disorder (P = 0.1935);Loss of disorder (P = 0.1935);Loss of disorder (P = 0.1935);Loss of disorder (P = 0.1935);.;Loss of disorder (P = 0.1935);Loss of disorder (P = 0.1935);Loss of disorder (P = 0.1935);.;Loss of disorder (P = 0.1935);Loss of disorder (P = 0.1935);Loss of disorder (P = 0.1935);.;Loss of disorder (P = 0.1935);Loss of disorder (P = 0.1935);Loss of disorder (P = 0.1935);Loss of disorder (P = 0.1935);Loss of disorder (P = 0.1935);
MVP
0.38
MPC
0.95
ClinPred
0.039
T
GERP RS
-5.8
Varity_R
0.067
gMVP
0.48

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs34299874; hg19: chr3-11061962; API