12-6867505-T-G

Position:

• chr12-6867505-T-G

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM1 BP4_Strong BS1_Supporting BS2

The NM_001159287.1(TPI1):​c.50T>G​(p.Ile17Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.003 in 1,579,330 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0038 (2 hom., cov: 34)
  • Exomes 𝑓: 0.0029 (11 hom.)
• Consequence: TPI1 NM_001159287.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 2.12

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 Benign. Variant got -7 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_001159287.1
• BP4: Computational evidence support a benign effect (MetaRNN=0.008082598).
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00377 (573/152082) while in subpopulation AFR AF= 0.00755 (313/41482). AF 95% confidence interval is 0.00686. There are 2 homozygotes in gnomad4. There are 269 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TPI1	NM_001159287.1	c.50T>G	p.Ile17Arg	missense_variant	1/7		NP_001152759.1
TPI1	NM_000365.6	c.-62T>G		upstream_gene_variant		ENST00000396705.10	NP_000356.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TPI1	ENST00000229270.8	c.50T>G	p.Ile17Arg	missense_variant	1/7	1		ENSP00000229270.4
TPI1	ENST00000613953.4	c.50T>G	p.Ile17Arg	missense_variant	1/7	1		ENSP00000484435.1
TPI1	ENST00000396705.10	c.-62T>G		upstream_gene_variant		1	NM_000365.6	ENSP00000379933.4

Frequencies

GnomAD3 genomes AF: 0.00379 AC: 576 AN: 151968 Hom.: 2 Cov.: 34

Gnomad AFR AF: 0.00754

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00307

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.000284

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00262

Gnomad OTH AF: 0.00669

GnomAD3 exomes AF: 0.00210 AC: 405 AN: 193188 Hom.: 0 AF XY: 0.00218 AC XY: 230 AN XY: 105348

Gnomad AFR exome AF: 0.00611

Gnomad AMR exome AF: 0.00250

Gnomad ASJ exome AF: 0.00236

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00114

Gnomad FIN exome AF: 0.000389

Gnomad NFE exome AF: 0.00233

Gnomad OTH exome AF: 0.00461

GnomAD4 exome AF: 0.00291 AC: 4160 AN: 1427248 Hom.: 11 Cov.: 34 AF XY: 0.00299 AC XY: 2111 AN XY: 707182

Gnomad4 AFR exome AF: 0.00766

Gnomad4 AMR exome AF: 0.00278

Gnomad4 ASJ exome AF: 0.00334

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00144

Gnomad4 FIN exome AF: 0.000481

Gnomad4 NFE exome AF: 0.00299

Gnomad4 OTH exome AF: 0.00381

GnomAD4 genome AF: 0.00377 AC: 573 AN: 152082 Hom.: 2 Cov.: 34 AF XY: 0.00362 AC XY: 269 AN XY: 74342

Gnomad4 AFR AF: 0.00755

Gnomad4 AMR AF: 0.00301

Gnomad4 ASJ AF: 0.00317

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.000284

Gnomad4 NFE AF: 0.00262

Gnomad4 OTH AF: 0.00662

Alfa AF: 0.00233 Hom.: 1

Bravo AF: 0.00410

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000778 AC: 3

ExAC AF: 0.00219 AC: 262

Asia WGS AF: 0.00260 AC: 9 AN: 3474

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 18, 2022	- -
Uncertain significance, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2024	TPI1: BP4, BS2 -

Triosephosphate isomerase deficiency Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Aug 10, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Uncertain	-0.070
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Benign	0.34	T;T
Eigen	Benign	0.082
Eigen_PC	Benign	0.16
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.51	.;T
MetaRNN	Benign	0.0081	T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.0	N;N
PROVEAN	Benign	-0.14	N;.
REVEL	Benign	0.21
Sift	Benign	0.16	T;.
Sift4G	Benign	0.11	T;T
Vest4		0.51
MVP		0.32
MPC		1.6
ClinPred		0.096	T
GERP RS		4.8
Varity_R		0.21
gMVP		0.37

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1800202; hg19: chr12-6976669;