12-6867639-C-T

Variant names:

• chr12-6867639-C-T
• NM_000365.6:c.73C>T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP3_Moderate

The NM_000365.6(TPI1):​c.73C>T​(p.Leu25Phe) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 34)
• Consequence: TPI1 NM_000365.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.49

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a chain Triosephosphate isomerase (size 247) in uniprot entity TPIS_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_000365.6
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.917

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TPI1	NM_000365.6	c.73C>T	p.Leu25Phe	missense_variant	Exon 1 of 7	ENST00000396705.10	NP_000356.1
TPI1	NM_001159287.1	c.184C>T	p.Leu62Phe	missense_variant	Exon 1 of 7		NP_001152759.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TPI1	ENST00000396705.10	c.73C>T	p.Leu25Phe	missense_variant	Exon 1 of 7	1	NM_000365.6	ENSP00000379933.4
TPI1	ENST00000229270.8	c.184C>T	p.Leu62Phe	missense_variant	Exon 1 of 7	1		ENSP00000229270.4
TPI1	ENST00000613953.4	c.184C>T	p.Leu62Phe	missense_variant	Exon 1 of 7	1		ENSP00000484435.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 34

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

May 23, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant has not been reported in the literature in individuals affected with TPI1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 25 of the TPI1 protein (p.Leu25Phe). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.72
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.16
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.93	D;D;.
Eigen	Benign	0.098
Eigen_PC	Benign	0.21
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	.;D;D
M_CAP	Pathogenic	0.77	D
MetaRNN	Pathogenic	0.92	D;D;D
MetaSVM	Uncertain	0.56	D
MutationAssessor	Benign	1.2	L;L;.
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-2.5	D;.;D
REVEL	Pathogenic	0.74
Sift	Benign	0.036	D;.;D
Sift4G	Uncertain	0.035	D;D;D
Polyphen		0.17	B;B;.
Vest4		0.58
MutPred		0.76		Gain of MoRF binding (P = 0.1405);Gain of MoRF binding (P = 0.1405);.;
MVP		0.81
MPC		1.2
ClinPred		0.98	D
GERP RS		5.2
Varity_R		0.84
gMVP		0.65

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-6976803;