chr3-10819744-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_014229.3(SLC6A11):​c.424C>T​(p.His142Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000129 in 1,614,100 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000085 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00013 ( 0 hom. )

Consequence

SLC6A11
NM_014229.3 missense

Scores

1
1
17

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.34
Variant links:
Genes affected
SLC6A11 (HGNC:11044): (solute carrier family 6 member 11) The protein encoded by this gene is a sodium-dependent transporter that uptakes gamma-aminobutyric acid (GABA), an inhibitory neurotransmitter, which ends the GABA neurotransmission. Defects in this gene may result in epilepsy, behavioral problems, or intellectual problems. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2015]

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.06377053).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
SLC6A11NM_014229.3 linkuse as main transcriptc.424C>T p.His142Tyr missense_variant 3/14 ENST00000254488.7 NP_055044.1
SLC6A11NM_001317406.3 linkuse as main transcriptc.424C>T p.His142Tyr missense_variant 3/4 NP_001304335.1
SLC6A11XM_011534033.3 linkuse as main transcriptc.424C>T p.His142Tyr missense_variant 3/9 XP_011532335.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
SLC6A11ENST00000254488.7 linkuse as main transcriptc.424C>T p.His142Tyr missense_variant 3/141 NM_014229.3 ENSP00000254488 P1P48066-1
SLC6A11ENST00000454147.1 linkuse as main transcriptc.424C>T p.His142Tyr missense_variant 3/41 ENSP00000404120 P48066-2

Frequencies

GnomAD3 genomes
AF:
0.0000854
AC:
13
AN:
152232
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.000288
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000147
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.000123
AC:
31
AN:
251434
Hom.:
0
AF XY:
0.0000957
AC XY:
13
AN XY:
135886
show subpopulations
Gnomad AFR exome
AF:
0.0000615
Gnomad AMR exome
AF:
0.0000289
Gnomad ASJ exome
AF:
0.000397
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000211
Gnomad OTH exome
AF:
0.000163
GnomAD4 exome
AF:
0.000133
AC:
195
AN:
1461868
Hom.:
0
Cov.:
32
AF XY:
0.000139
AC XY:
101
AN XY:
727232
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.000153
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.0000187
Gnomad4 NFE exome
AF:
0.000165
Gnomad4 OTH exome
AF:
0.0000662
GnomAD4 genome
AF:
0.0000854
AC:
13
AN:
152232
Hom.:
0
Cov.:
33
AF XY:
0.0000538
AC XY:
4
AN XY:
74372
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.000288
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000147
Gnomad4 OTH
AF:
0.000478
Alfa
AF:
0.000182
Hom.:
1
Bravo
AF:
0.0000491
TwinsUK
AF:
0.00
AC:
0
ALSPAC
AF:
0.000259
AC:
1
ESP6500AA
AF:
0.000227
AC:
1
ESP6500EA
AF:
0.000233
AC:
2
ExAC
AF:
0.000123
AC:
15
EpiCase
AF:
0.000436
EpiControl
AF:
0.000119

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsJan 22, 2024The c.424C>T (p.H142Y) alteration is located in exon 3 (coding exon 3) of the SLC6A11 gene. This alteration results from a C to T substitution at nucleotide position 424, causing the histidine (H) at amino acid position 142 to be replaced by a tyrosine (Y). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.12
BayesDel_addAF
Benign
-0.30
T
BayesDel_noAF
Benign
-0.39
CADD
Benign
20
DANN
Benign
0.66
DEOGEN2
Benign
0.036
T;.
Eigen
Benign
-0.64
Eigen_PC
Benign
-0.32
FATHMM_MKL
Uncertain
0.93
D
LIST_S2
Benign
0.84
T;T
M_CAP
Benign
0.010
T
MetaRNN
Benign
0.064
T;T
MetaSVM
Benign
-0.92
T
MutationAssessor
Benign
-1.1
N;N
MutationTaster
Benign
1.0
D;D
PrimateAI
Pathogenic
0.82
D
PROVEAN
Benign
1.8
N;N
REVEL
Benign
0.11
Sift
Benign
1.0
T;T
Sift4G
Benign
1.0
T;T
Polyphen
0.0
B;.
Vest4
0.36
MVP
0.53
MPC
0.73
ClinPred
0.033
T
GERP RS
4.4
Varity_R
0.17
gMVP
0.67

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: rs144440521; hg19: chr3-10861429; API