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rs771439149

chr3-11033648-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP2BP6BS1BS2

The NM_003042.4(SLC6A1):c.1436G>A(p.Arg479Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000478 in 1,609,326 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. R479R) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000047 ( 0 hom. )

Consequence

SLC6A1
NM_003042.4 missense

Scores

1
9
4

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: 5.80
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

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
BP6
?
    BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 3-11033648-G-A is Benign according to our data. Variant chr3-11033648-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 542200.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=1}.
BS1
?
    BS1 - Allele frequency is greater than expected for disorder
Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.0000474 (69/1457162) while in subpopulation MID AF= 0.00279 (16/5744). AF 95% confidence interval is 0.00175. There are 0 homozygotes in gnomad4_exome. There are 29 alleles in male gnomad4_exome subpopulation. Median coverage is 28. This position pass quality control queck.
BS2
?
    BS2 - Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age
High AC in GnomAd at 8 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
SLC6A1NM_003042.4 linkuse as main transcriptc.1436G>A p.Arg479Gln missense_variant 14/16 ENST00000287766.10

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
SLC6A1ENST00000287766.10 linkuse as main transcriptc.1436G>A p.Arg479Gln missense_variant 14/161 NM_003042.4 P1

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.0000526
AC:
8
AN:
152164
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000131
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:
0.0000735
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000718
AC:
18
AN:
250786
Hom.:
0
AF XY:
0.0000664
AC XY:
9
AN XY:
135532
show subpopulations
Gnomad AFR exome
AF:
0.0000615
Gnomad AMR exome
AF:
0.000261
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:
0.0000617
Gnomad OTH exome
AF:
0.000163
GnomAD4 exome
AF:
0.0000474
AC:
69
AN:
1457162
Hom.:
0
Cov.:
28
AF XY:
0.0000400
AC XY:
29
AN XY:
725156
show subpopulations
Gnomad4 AFR exome
AF:
0.0000898
Gnomad4 AMR exome
AF:
0.000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000232
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000325
Gnomad4 OTH exome
AF:
0.0000332
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.0000526
AC:
8
AN:
152164
Hom.:
0
Cov.:
32
AF XY:
0.0000404
AC XY:
3
AN XY:
74322
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.000131
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000735
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000676
Hom.:
0
Bravo
AF:
0.0000416
ExAC
?
    Exome Aggregation Consortium database
AF:
0.0000659
AC:
8
EpiCase
AF:
0.000218
EpiControl
AF:
0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsApr 12, 2018The p.R479Q variant (also known as c.1436G>A), located in coding exon 12 of the SLC6A1 gene, results from a G to A substitution at nucleotide position 1436. The arginine at codon 479 is replaced by glutamine, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Myoclonic-astatic epilepsy Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsOct 31, 2018- -
Myoclonic-atonic epilepsy Benign:1
Likely benign, criteria provided, single submitterclinical testingInvitaeDec 07, 2023- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.21
BayesDel_addAF
Benign
-0.14
T
BayesDel_noAF
Benign
-0.13
Cadd
Pathogenic
32
Dann
Pathogenic
1.0
DEOGEN2
Uncertain
0.52
D;D;D;D;D;.;D;.;D;D;D;D;.;D;D;D;.;D;D;D;.;D;D;D;.
Eigen
Uncertain
0.61
Eigen_PC
Uncertain
0.61
FATHMM_MKL
Uncertain
0.93
D
M_CAP
Uncertain
0.14
D
MetaRNN
Uncertain
0.58
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
0.030
D
MutationAssessor
Uncertain
2.2
M;M;M;M;M;.;M;.;M;M;M;M;.;M;M;M;.;M;M;M;.;M;M;M;.
MutationTaster
Benign
1.0
D;D
PrimateAI
Uncertain
0.62
T
Polyphen
0.98
D;D;D;D;D;.;D;.;D;D;D;D;.;D;D;D;.;D;D;D;.;D;D;D;.
Vest4
0.45
MutPred
0.75
Loss of stability (P = 0.1822);Loss of stability (P = 0.1822);Loss of stability (P = 0.1822);Loss of stability (P = 0.1822);Loss of stability (P = 0.1822);.;Loss of stability (P = 0.1822);.;Loss of stability (P = 0.1822);Loss of stability (P = 0.1822);Loss of stability (P = 0.1822);Loss of stability (P = 0.1822);.;Loss of stability (P = 0.1822);Loss of stability (P = 0.1822);Loss of stability (P = 0.1822);.;Loss of stability (P = 0.1822);Loss of stability (P = 0.1822);Loss of stability (P = 0.1822);.;Loss of stability (P = 0.1822);Loss of stability (P = 0.1822);Loss of stability (P = 0.1822);.;
MVP
0.90
MPC
2.3
ClinPred
0.43
T
GERP RS
5.1
Varity_R
0.55
gMVP
0.74

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: rs771439149; hg19: chr3-11075334; COSMIC: COSV55113653; COSMIC: COSV55113653; API