chr3-11017239-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2PP2BP4_Moderate

The NM_003042.4(SLC6A1):​c.28G>A​(p.Asp10Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000031 in 1,613,692 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. D10D) has been classified as Benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

SLC6A1
NM_003042.4 missense

Scores

1
2
16

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 7.49
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]
SLC6A1-AS1 (HGNC:40546): (SLC6A1 antisense RNA 1)

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 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=0.21550986).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
SLC6A1NM_003042.4 linkuse as main transcriptc.28G>A p.Asp10Asn missense_variant 3/16 ENST00000287766.10
SLC6A1-AS1NR_046647.1 linkuse as main transcriptn.105+1881C>T intron_variant, non_coding_transcript_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
SLC6A1ENST00000287766.10 linkuse as main transcriptc.28G>A p.Asp10Asn missense_variant 3/161 NM_003042.4 P1
SLC6A1-AS1ENST00000414969.2 linkuse as main transcriptn.105+1881C>T intron_variant, non_coding_transcript_variant 4

Frequencies

GnomAD3 genomes
AF:
0.00000658
AC:
1
AN:
151946
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
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:
0.00
GnomAD3 exomes
AF:
0.00000797
AC:
2
AN:
250926
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
135766
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:
0.0000176
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000274
AC:
4
AN:
1461746
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
727178
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:
0.00000360
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000658
AC:
1
AN:
151946
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74196
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
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:
0.00
Alfa
AF:
0.0000712
Hom.:
0
Bravo
AF:
0.00000378
ExAC
AF:
0.0000165
AC:
2

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsNov 21, 2022The c.28G>A (p.D10N) alteration is located in exon 3 (coding exon 1) of the SLC6A1 gene. This alteration results from a G to A substitution at nucleotide position 28, causing the aspartic acid (D) at amino acid position 10 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
Myoclonic-atonic epilepsy Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpApr 19, 2021In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt SLC6A1 protein function. This variant has not been reported in the literature in individuals with SLC6A1-related conditions. This variant is present in population databases (rs751108300, ExAC 0.003%). This sequence change replaces aspartic acid with asparagine at codon 10 of the SLC6A1 protein (p.Asp10Asn). The aspartic acid residue is moderately conserved and there is a small physicochemical difference between aspartic acid and asparagine. -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenApr 01, 2023SLC6A1: PP2 -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.11
BayesDel_addAF
Benign
-0.043
T
BayesDel_noAF
Benign
-0.28
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Benign
0.26
T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;.;T;.;T;T;.;.;.
Eigen
Benign
-0.058
Eigen_PC
Benign
0.14
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Benign
0.27
.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;T;T;T;T
M_CAP
Benign
0.023
T
MetaRNN
Benign
0.22
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
-0.83
T
MutationAssessor
Benign
0.55
N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;.;N;.;N;N;.;.;.
MutationTaster
Benign
1.0
D;D
PrimateAI
Uncertain
0.67
T
PROVEAN
Benign
-0.63
.;N;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
REVEL
Benign
0.19
Sift
Benign
0.10
.;T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G
Benign
0.067
.;T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Polyphen
0.14
B;B;B;B;B;B;B;B;B;B;B;B;B;B;B;B;.;B;.;B;B;.;.;.
Vest4
0.50
MutPred
0.21
Gain of MoRF binding (P = 0.0213);Gain of MoRF binding (P = 0.0213);Gain of MoRF binding (P = 0.0213);Gain of MoRF binding (P = 0.0213);Gain of MoRF binding (P = 0.0213);Gain of MoRF binding (P = 0.0213);Gain of MoRF binding (P = 0.0213);Gain of MoRF binding (P = 0.0213);Gain of MoRF binding (P = 0.0213);Gain of MoRF binding (P = 0.0213);Gain of MoRF binding (P = 0.0213);Gain of MoRF binding (P = 0.0213);Gain of MoRF binding (P = 0.0213);Gain of MoRF binding (P = 0.0213);Gain of MoRF binding (P = 0.0213);Gain of MoRF binding (P = 0.0213);Gain of MoRF binding (P = 0.0213);Gain of MoRF binding (P = 0.0213);Gain of MoRF binding (P = 0.0213);Gain of MoRF binding (P = 0.0213);Gain of MoRF binding (P = 0.0213);Gain of MoRF binding (P = 0.0213);Gain of MoRF binding (P = 0.0213);Gain of MoRF binding (P = 0.0213);
MVP
0.84
MPC
1.0
ClinPred
0.66
D
GERP RS
4.4
Varity_R
0.082
gMVP
0.70

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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: rs751108300; hg19: chr3-11058925; API