Genetic Variant ENST00000229270.8:c.112A>T (chr12-6867567-A-T) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP2PP3

The ENST00000229270.8(TPI1):c.112A>T(p.Met38Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,459,994 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M38V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

TPI1
ENST00000229270.8 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.92

Publications

3 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.826

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TPI1	NM_000365.6 link	c.1A>T	p.Met1?	initiator_codon_variant	Exon 1 of 7	ENST00000396705.10	NP_000356.1	P60174-1V9HWK1Q53HE2
TPI1	NM_001159287.1 link	c.112A>T	p.Met38Leu	missense_variant	Exon 1 of 7		NP_001152759.1	P60174-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TPI1	ENST00000229270.8 link	c.112A>T	p.Met38Leu	missense_variant	Exon 1 of 7	1		ENSP00000229270.4	P60174-3
TPI1	ENST00000613953.4 link	c.112A>T	p.Met38Leu	missense_variant	Exon 1 of 7	1		ENSP00000484435.1	P60174-3
TPI1	ENST00000396705.10 link	c.1A>T	p.Met1?	initiator_codon_variant	Exon 1 of 7	1	NM_000365.6	ENSP00000379933.4	P60174-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000408

AC:

AN:

244966

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

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:

0.00000907

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1459994

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726276

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33406

American (AMR)

AF:

0.00

AC:

AN:

44620

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26106

East Asian (EAS)

AF:

0.00

AC:

AN:

39672

South Asian (SAS)

AF:

0.00

AC:

AN:

86142

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52448

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1111570

Other (OTH)

AF:

0.00

AC:

AN:

60268

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.550

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000826

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.26

BayesDel_noAF

Uncertain

0.13

CADD

Uncertain

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.41

T;T;.

Eigen

Uncertain

0.32

Eigen_PC

Uncertain

0.33

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.69

.;T;D

M_CAP

Pathogenic

0.58

MetaRNN

Uncertain

0.72

D;D;D

MetaSVM

Uncertain

0.43

MutationAssessor

Benign

0.0

N;N;.

PhyloP100

3.9

PROVEAN

Benign

-0.78

N;.;N

REVEL

Pathogenic

0.68

Sift

Uncertain

0.0010

D;.;D

Sift4G

Benign

0.21

T;T;T

Polyphen

0.91

P;P;.

Vest4

0.47

MutPred

0.58

Loss of MoRF binding (P = 0.0744);Loss of MoRF binding (P = 0.0744);.;

MVP

0.87

MPC

0.37

ClinPred

0.62

GERP RS

4.1

PromoterAI

-0.75

Under-expression

(source)

Varity_R

0.92

gMVP

0.35

Mutation Taster

=35/165

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over