12-6867538-C-G

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 3P and 13B. PM1PP2BP4_StrongBP6BS1BS2

The NM_001159287.1(TPI1):​c.83C>G​(p.Thr28Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000837 in 1,608,602 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T28I) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00056 ( 1 hom., cov: 34)
Exomes 𝑓: 0.00087 ( 12 hom. )

Consequence

TPI1
NM_001159287.1 missense

Scores

1
15

Clinical Significance

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

Conservation

PhyloP100: 1.03
Variant links:
Genes affected
TPI1 (HGNC:12009): (triosephosphate isomerase 1) This gene encodes an enzyme, consisting of two identical proteins, which catalyzes the isomerization of glyceraldehydes 3-phosphate (G3P) and dihydroxy-acetone phosphate (DHAP) in glycolysis and gluconeogenesis. Mutations in this gene are associated with triosephosphate isomerase deficiency. Pseudogenes have been identified on chromosomes 1, 4, 6 and 7. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Apr 2009]

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

PM1
In a chain Triosephosphate isomerase (size 247) in uniprot entity TPIS_HUMAN there are 8 pathogenic changes around while only 3 benign (73%) in NM_001159287.1
PP2
Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 5 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: -0.22304 (below the threshold of 3.09). Trascript score misZ: 0.73719 (below the threshold of 3.09). GenCC associations: The gene is linked to triosephosphate isomerase deficiency.
BP4
Computational evidence support a benign effect (MetaRNN=0.004826635).
BP6
Variant 12-6867538-C-G is Benign according to our data. Variant chr12-6867538-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1330976.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=1}.
BS1
Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000558 (85/152332) while in subpopulation SAS AF = 0.0108 (52/4832). AF 95% confidence interval is 0.00843. There are 1 homozygotes in GnomAd4. There are 45 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position FAILED quality control check.
BS2
High Homozygotes in GnomAdExome4 at 12 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TPI1NM_000365.6 linkc.-29C>G 5_prime_UTR_variant Exon 1 of 7 ENST00000396705.10 NP_000356.1 P60174-1V9HWK1Q53HE2
TPI1NM_001159287.1 linkc.83C>G p.Thr28Ser missense_variant Exon 1 of 7 NP_001152759.1 P60174-3

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TPI1ENST00000229270.8 linkc.83C>G p.Thr28Ser missense_variant Exon 1 of 7 1 ENSP00000229270.4 P60174-3
TPI1ENST00000613953.4 linkc.83C>G p.Thr28Ser missense_variant Exon 1 of 7 1 ENSP00000484435.1 P60174-3
TPI1ENST00000396705 linkc.-29C>G 5_prime_UTR_variant Exon 1 of 7 1 NM_000365.6 ENSP00000379933.4 P60174-1

Frequencies

GnomAD3 genomes
AF:
0.000578
AC:
88
AN:
152220
Hom.:
2
Cov.:
34
show subpopulations
Gnomad AFR
AF:
0.0000482
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.000576
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.0114
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000397
Gnomad OTH
AF:
0.000955
GnomAD2 exomes
AF:
0.00159
AC:
377
AN:
236626
AF XY:
0.00197
show subpopulations
Gnomad AFR exome
AF:
0.000145
Gnomad AMR exome
AF:
0.000300
Gnomad ASJ exome
AF:
0.00185
Gnomad EAS exome
AF:
0.0000568
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000700
Gnomad OTH exome
AF:
0.00139
GnomAD4 exome
AF:
0.000866
AC:
1261
AN:
1456270
Hom.:
12
Cov.:
34
AF XY:
0.00110
AC XY:
795
AN XY:
724190
show subpopulations
Gnomad4 AFR exome
AF:
0.000150
AC:
5
AN:
33304
Gnomad4 AMR exome
AF:
0.000228
AC:
10
AN:
43852
Gnomad4 ASJ exome
AF:
0.00135
AC:
35
AN:
26008
Gnomad4 EAS exome
AF:
0.0000506
AC:
2
AN:
39536
Gnomad4 SAS exome
AF:
0.00805
AC:
690
AN:
85686
Gnomad4 FIN exome
AF:
0.00
AC:
0
AN:
52060
Gnomad4 NFE exome
AF:
0.000411
AC:
456
AN:
1109952
Gnomad4 Remaining exome
AF:
0.000898
AC:
54
AN:
60120
Heterozygous variant carriers
0
81
162
244
325
406
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Exome Het
Exome Hom
Variant carriers
0
24
48
72
96
120
<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:
0.000558
AC:
85
AN:
152332
Hom.:
1
Cov.:
34
AF XY:
0.000604
AC XY:
45
AN XY:
74488
show subpopulations
Gnomad4 AFR
AF:
0.0000481
AC:
0.0000481
AN:
0.0000481
Gnomad4 AMR
AF:
0.00
AC:
0
AN:
0
Gnomad4 ASJ
AF:
0.000576
AC:
0.000576037
AN:
0.000576037
Gnomad4 EAS
AF:
0.00
AC:
0
AN:
0
Gnomad4 SAS
AF:
0.0108
AC:
0.0107616
AN:
0.0107616
Gnomad4 FIN
AF:
0.00
AC:
0
AN:
0
Gnomad4 NFE
AF:
0.000397
AC:
0.000396919
AN:
0.000396919
Gnomad4 OTH
AF:
0.000945
AC:
0.00094518
AN:
0.00094518
Heterozygous variant carriers
0
6
13
19
26
32
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Genome Het
Genome Hom
Variant carriers
0
2
4
6
8
10
<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:
0.000359
Hom.:
0
Bravo
AF:
0.000340
TwinsUK
AF:
0.000270
AC:
1
ALSPAC
AF:
0.000259
AC:
1
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000466
AC:
4
ExAC
AF:
0.00165
AC:
200
Asia WGS
AF:
0.00231
AC:
8
AN:
3476

ClinVar

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

Submissions by phenotype

not provided Uncertain:1Benign:1
-
Breakthrough Genomics, Breakthrough Genomics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:not provided

- -

Jun 01, 2024
CeGaT Center for Human Genetics Tuebingen
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

TPI1: BP4, BS2 -

Triosephosphate isomerase deficiency Uncertain:1
Jul 26, 2021
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Benign
-0.54
T
BayesDel_noAF
Benign
-0.55
CADD
Benign
16
DANN
Uncertain
0.98
DEOGEN2
Benign
0.31
T;T
Eigen
Benign
-0.57
Eigen_PC
Benign
-0.55
FATHMM_MKL
Benign
0.73
D
LIST_S2
Benign
0.26
.;T
MetaRNN
Benign
0.0048
T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
0.0
N;N
PROVEAN
Benign
-0.020
N;.
REVEL
Benign
0.019
Sift
Benign
0.62
T;.
Sift4G
Benign
0.72
T;T
Vest4
0.039
MutPred
0.17
Gain of disorder (P = 0.0357);Gain of disorder (P = 0.0357);
MVP
0.12
MPC
0.34
ClinPred
0.0098
T
GERP RS
2.6
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.0
Varity_R
0.086
gMVP
0.17
Mutation Taster
=297/3
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

LitVar

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

Other links and lift over

dbSNP: rs181882616; hg19: chr12-6976702; API