12-6867567-A-T

Variant names:

• chr12-6867567-A-T
• rs201432576
• ENST00000229270.8:c.112A>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP2 PP3

The NM_001159287.1(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 NM_001159287.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.92
• Publications: 3 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: 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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001159287.1. 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.1A>T	p.Met1?	initiator_codon	Exon 1 of 7	NP_000356.1	P60174-1
	TPI1	NM_001159287.1		c.112A>T	p.Met38Leu	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.112A>T	p.Met38Leu	missense	Exon 1 of 7	ENSP00000229270.4	P60174-3
	TPI1	ENST00000613953.4	TSL:1	c.112A>T	p.Met38Leu	missense	Exon 1 of 7	ENSP00000484435.1	P60174-3
	TPI1	ENST00000396705.10	TSL:1 MANE Select	c.1A>T	p.Met1?	initiator_codon	Exon 1 of 7	ENSP00000379933.4	P60174-1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD2 exomes AF: 0.00000408 AC: 1 AN: 244966 AF XY: 0.00

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: 2 AN: 1459994 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 726276

African (AFR) AF: 0.00 AC: 0 AN: 33406

American (AMR) AF: 0.00 AC: 0 AN: 44620

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26106

East Asian (EAS) AF: 0.00 AC: 0 AN: 39672

South Asian (SAS) AF: 0.00 AC: 0 AN: 86142

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52448

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111570

Other (OTH) AF: 0.00 AC: 0 AN: 60268

GnomAD4 genome Cov.: 34

ExAC AF: 0.00000826 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Uncertain	0.13
CADD	Uncertain	24
DANN	Benign	0.94
DEOGEN2	Benign	0.41	T
Eigen	Uncertain	0.32
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.69	T
M_CAP	Pathogenic	0.58	D
MetaRNN	Uncertain	0.72	D
MetaSVM	Uncertain	0.43	D
MutationAssessor	Benign	0.0	N
PhyloP100		3.9
PROVEAN	Benign	-0.78	N
REVEL	Pathogenic	0.68
Sift	Uncertain	0.0010	D
Sift4G	Benign	0.21	T
Polyphen		0.91	P
Vest4		0.47
MutPred		0.58		Loss of MoRF binding (P = 0.0744)
MVP		0.87
MPC		0.37
ClinPred		0.62	D
GERP RS		4.1
PromoterAI		-0.75	Under-expression
Varity_R		0.92
gMVP		0.35
Mutation Taster		=35/165	disease causing

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

Other links and lift over

dbSNP: rs201432576; hg19: chr12-6976731; COSMIC: COSV57540147; COSMIC: COSV57540147;