rs387906513

Variant names:

• chr12-6869181-G-T
• rs387906513
• NM_000365.6:c.322G>T

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_000365.6(TPI1):​c.322G>T​(p.Glu108*) variant causes a stop gained, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TPI1 NM_000365.6 stop_gained, splice_region
• Scores: Splicing: ADA: 0.8450
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.71
• Publications: 2 publications found

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

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TPI1	NM_000365.6	c.322G>T	p.Glu108*	stop_gained, splice_region_variant	Exon 3 of 7	ENST00000396705.10	NP_000356.1
TPI1	NM_001159287.1	c.433G>T	p.Glu145*	stop_gained, splice_region_variant	Exon 3 of 7		NP_001152759.1
TPI1	NM_001258026.2	c.76G>T	p.Glu26*	stop_gained, splice_region_variant	Exon 3 of 7		NP_001244955.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TPI1	ENST00000396705.10	c.322G>T	p.Glu108*	stop_gained, splice_region_variant	Exon 3 of 7	1	NM_000365.6	ENSP00000379933.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	53
DANN	Uncertain	1.0
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.97
FATHMM_MKL	Pathogenic	0.99	D
PhyloP100		9.7
Vest4		0.93
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=3/197	disease causing (fs/PTC)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.84
dbscSNV1_RF	Pathogenic	0.80
SpliceAI score (max)		0.46		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.46		Position offset: 2

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

Other links and lift over

dbSNP: rs387906513; hg19: chr12-6978345;