chr3-10934147-T-C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_014229.3(SLC6A11):​c.1556T>C​(p.Met519Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00194 in 1,613,182 control chromosomes in the GnomAD database, including 55 homozygotes. 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 Benign (★★).

Frequency

Genomes: 𝑓 0.010 ( 28 hom., cov: 32)
Exomes 𝑓: 0.0011 ( 27 hom. )

Consequence

SLC6A11
NM_014229.3 missense

Scores

2
16

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 7.53

Publications

2 publications found
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]

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.007879078).
BP6
Variant 3-10934147-T-C is Benign according to our data. Variant chr3-10934147-T-C is described in CliVar as Benign. Clinvar id is 716099.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-10934147-T-C is described in CliVar as Benign. Clinvar id is 716099.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-10934147-T-C is described in CliVar as Benign. Clinvar id is 716099.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS1
Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0104 (1583/152314) while in subpopulation AFR AF = 0.036 (1496/41562). AF 95% confidence interval is 0.0345. There are 28 homozygotes in GnomAd4. There are 718 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
BS2
High Homozygotes in GnomAd4 at 28 gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SLC6A11NM_014229.3 linkc.1556T>C p.Met519Thr missense_variant Exon 12 of 14 ENST00000254488.7 NP_055044.1 P48066-1
SLC6A11XM_047448764.1 linkc.1034T>C p.Met345Thr missense_variant Exon 10 of 12 XP_047304720.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SLC6A11ENST00000254488.7 linkc.1556T>C p.Met519Thr missense_variant Exon 12 of 14 1 NM_014229.3 ENSP00000254488.2 P48066-1
SLC6A11ENST00000464828.1 linkn.182T>C non_coding_transcript_exon_variant Exon 1 of 2 3
ENSG00000286962ENST00000656787.1 linkn.350+2843A>G intron_variant Intron 3 of 3

Frequencies

GnomAD3 genomes
AF:
0.0104
AC:
1578
AN:
152196
Hom.:
28
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0360
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00366
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00316
Gnomad NFE
AF:
0.0000588
Gnomad OTH
AF:
0.0120
GnomAD2 exomes
AF:
0.00253
AC:
636
AN:
251372
AF XY:
0.00203
show subpopulations
Gnomad AFR exome
AF:
0.0354
Gnomad AMR exome
AF:
0.00127
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000528
Gnomad OTH exome
AF:
0.000978
GnomAD4 exome
AF:
0.00106
AC:
1545
AN:
1460868
Hom.:
27
Cov.:
30
AF XY:
0.000947
AC XY:
688
AN XY:
726856
show subpopulations
African (AFR)
AF:
0.0389
AC:
1300
AN:
33456
American (AMR)
AF:
0.00136
AC:
61
AN:
44724
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26122
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39692
South Asian (SAS)
AF:
0.000151
AC:
13
AN:
86232
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53416
Middle Eastern (MID)
AF:
0.000173
AC:
1
AN:
5768
European-Non Finnish (NFE)
AF:
0.0000126
AC:
14
AN:
1111098
Other (OTH)
AF:
0.00258
AC:
156
AN:
60360
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.470
Heterozygous variant carriers
0
69
139
208
278
347
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Exome Hom
Variant carriers
0
42
84
126
168
210
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.0104
AC:
1583
AN:
152314
Hom.:
28
Cov.:
32
AF XY:
0.00964
AC XY:
718
AN XY:
74472
show subpopulations
African (AFR)
AF:
0.0360
AC:
1496
AN:
41562
American (AMR)
AF:
0.00366
AC:
56
AN:
15304
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3470
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5176
South Asian (SAS)
AF:
0.000207
AC:
1
AN:
4830
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10624
Middle Eastern (MID)
AF:
0.00340
AC:
1
AN:
294
European-Non Finnish (NFE)
AF:
0.0000588
AC:
4
AN:
68028
Other (OTH)
AF:
0.0118
AC:
25
AN:
2114
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.505
Heterozygous variant carriers
0
80
159
239
318
398
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Genome Hom
Variant carriers
0
20
40
60
80
100
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.00432
Hom.:
24
Bravo
AF:
0.0120
ESP6500AA
AF:
0.0359
AC:
158
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.00290
AC:
352
Asia WGS
AF:
0.00115
AC:
4
AN:
3478
EpiCase
AF:
0.00
EpiControl
AF:
0.000119

ClinVar

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

Submissions by phenotype

not provided Benign:2
-
Breakthrough Genomics, Breakthrough Genomics
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:not provided

- -

May 21, 2018
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.13
BayesDel_addAF
Benign
-0.51
T
BayesDel_noAF
Benign
-0.47
CADD
Benign
23
DANN
Benign
0.78
DEOGEN2
Benign
0.16
T
Eigen
Benign
-0.38
Eigen_PC
Benign
-0.18
FATHMM_MKL
Uncertain
0.95
D
LIST_S2
Uncertain
0.90
D
MetaRNN
Benign
0.0079
T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
-0.34
N
PhyloP100
7.5
PrimateAI
Benign
0.36
T
PROVEAN
Benign
-1.6
N
REVEL
Benign
0.21
Sift
Benign
0.34
T
Sift4G
Benign
0.26
T
Polyphen
0.0
B
Vest4
0.24
MVP
0.66
MPC
0.72
ClinPred
0.024
T
GERP RS
4.6
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.23
gMVP
0.70
Mutation Taster
=83/17
polymorphism

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

Other links and lift over

dbSNP: rs75951495; hg19: chr3-10975833; API