ENST00000229270.8:c.81C>A

Variant names:

• chr12-6867536-C-A
• ENST00000229270.8:c.81C>A
• TPI1 p.Asp27Glu

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 3P and 4B. PM2 PP2 BP4_Strong

The ENST00000229270.8(TPI1):​c.81C>A​(p.Asp27Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. D27D) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 34)
• Consequence: TPI1 ENST00000229270.8 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.72
• Publications: 0 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: PanelApp Australia, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -1 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.041980505).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000229270.8. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TPI1	NM_000365.6	MANE Select	c.-31C>A		5_prime_UTR	Exon 1 of 7	NP_000356.1	P60174-1
	TPI1	NM_001159287.1		c.81C>A	p.Asp27Glu	missense	Exon 1 of 7	NP_001152759.1	P60174-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TPI1	ENST00000229270.8	TSL:1	c.81C>A	p.Asp27Glu	missense	Exon 1 of 7	ENSP00000229270.4	P60174-3
	TPI1	ENST00000613953.4	TSL:1	c.81C>A	p.Asp27Glu	missense	Exon 1 of 7	ENSP00000484435.1	P60174-3
	TPI1	ENST00000396705.10	TSL:1 MANE Select	c.-31C>A		5_prime_UTR	Exon 1 of 7	ENSP00000379933.4	P60174-1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	1.4
DANN	Benign	0.94
DEOGEN2	Benign	0.30	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.33	N
LIST_S2	Benign	0.21	T
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.042	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.0	N
PhyloP100		-1.7
PROVEAN	Benign	-0.030	N
REVEL	Benign	0.0060
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
PromoterAI		-0.020	Neutral
Varity_R		0.041
gMVP		0.098
Mutation Taster		=95/5	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr12-6976700;