12-6867678-A-G

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM1PP2BP4

The NM_000365.6(TPI1):c.112A>G(p.Thr38Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00000809 in 1,606,234 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 34)

Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

TPI1
NM_000365.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.29

Publications

1 publications found

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]

TPI1 Gene-Disease associations (from GenCC):

triosephosphate isomerase deficiency
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet

TPI1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM1

In a chain Triosephosphate isomerase (size 247) in uniprot entity TPIS_HUMAN there are 5 pathogenic changes around while only 1 benign (83%) in NM_000365.6

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: 1.6741 (below the threshold of 3.09). GenCC associations: The gene is linked to triosephosphate isomerase deficiency.

BP4

Computational evidence support a benign effect (MetaRNN=0.27529863).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TPI1	NM_000365.6 link	c.112A>G	p.Thr38Ala	missense_variant	Exon 1 of 7	ENST00000396705.10	NP_000356.1	P60174-1V9HWK1Q53HE2
TPI1	NM_001159287.1 link	c.223A>G	p.Thr75Ala	missense_variant	Exon 1 of 7		NP_001152759.1	P60174-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TPI1	ENST00000396705.10 link	c.112A>G	p.Thr38Ala	missense_variant	Exon 1 of 7	1	NM_000365.6	ENSP00000379933.4	P60174-1
TPI1	ENST00000229270.8 link	c.223A>G	p.Thr75Ala	missense_variant	Exon 1 of 7	1		ENSP00000229270.4	P60174-3
TPI1	ENST00000613953.4 link	c.223A>G	p.Thr75Ala	missense_variant	Exon 1 of 7	1		ENSP00000484435.1	P60174-3

Frequencies

GnomAD3 genomes

AF:

0.0000331

AC:

AN:

151116

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000122

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000837

AC:

AN:

239008

AF XY:

0.0000152

show subpopulations

Gnomad AFR exome

AF:

0.000146

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000550

AC:

AN:

1455006

Hom.:

Cov.:

AF XY:

0.00000553

AC XY:

AN XY:

723724

show subpopulations

African (AFR)

AF:

0.000243

AC:

AN:

32904

American (AMR)

AF:

0.00

AC:

AN:

44346

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25892

East Asian (EAS)

AF:

0.00

AC:

AN:

39276

South Asian (SAS)

AF:

0.00

AC:

AN:

85646

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52142

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5724

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1109076

Other (OTH)

AF:

0.00

AC:

AN:

60000

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000331

AC:

AN:

151228

Hom.:

Cov.:

AF XY:

0.0000541

AC XY:

AN XY:

73910

show subpopulations

African (AFR)

AF:

0.000122

AC:

AN:

41116

American (AMR)

AF:

0.00

AC:

AN:

15212

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5066

South Asian (SAS)

AF:

0.00

AC:

AN:

4752

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10528

Middle Eastern (MID)

AF:

0.00

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67782

Other (OTH)

AF:

0.00

AC:

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000667

Hom.:

Bravo

AF:

0.0000491

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

May 20, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.112A>G (p.T38A) alteration is located in exon 1 (coding exon 1) of the TPI1 gene. This alteration results from a A to G substitution at nucleotide position 112, causing the threonine (T) at amino acid position 38 to be replaced by an alanine (A). 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

0.18

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.20

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Pathogenic

0.94

D;D;.

Eigen

Benign

-0.16

Eigen_PC

Benign

-0.015

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.72

.;T;T

M_CAP

Pathogenic

0.69

MetaRNN

Benign

0.28

T;T;T

MetaSVM

Uncertain

0.049

MutationAssessor

Benign

0.035

N;N;.

PhyloP100

4.3

PrimateAI

Uncertain

0.65

PROVEAN

Uncertain

-3.3

D;.;D

REVEL

Uncertain

0.39

Sift

Benign

0.085

T;.;T

Sift4G

Benign

0.24

T;T;T

Polyphen

0.0020

B;B;.

Vest4

0.23

MVP

0.64

MPC

0.50

ClinPred

0.16

GERP RS

4.0

PromoterAI

-0.021

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.47

gMVP

0.61

Mutation Taster

=53/47

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

12-6867678-A-G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over