12-6867618-C-G

Variant names:

• chr12-6867618-C-G
• NM_000365.6:c.52C>G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1 PM2 BP4

The NM_000365.6(TPI1):​c.52C>G​(p.Arg18Gly) 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. 12/21 in silico tools predict a benign 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: 0.537

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 Uncertain_significance. Variant got 3 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
• BP4: Computational evidence support a benign effect (MetaRNN=0.31548452).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TPI1	NM_000365.6	c.52C>G	p.Arg18Gly	missense_variant	Exon 1 of 7	ENST00000396705.10	NP_000356.1
TPI1	NM_001159287.1	c.163C>G	p.Arg55Gly	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.52C>G	p.Arg18Gly	missense_variant	Exon 1 of 7	1	NM_000365.6	ENSP00000379933.4
TPI1	ENST00000229270.8	c.163C>G	p.Arg55Gly	missense_variant	Exon 1 of 7	1		ENSP00000229270.4
TPI1	ENST00000613953.4	c.163C>G	p.Arg55Gly	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

Inborn genetic diseases Uncertain:1

Dec 10, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.52C>G (p.R18G) alteration is located in exon 1 (coding exon 1) of the TPI1 gene. This alteration results from a C to G substitution at nucleotide position 52, causing the arginine (R) at amino acid position 18 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Uncertain	0.075	D
BayesDel_noAF	Benign	-0.13
CADD	Benign	18
DANN	Benign	0.88
DEOGEN2	Uncertain	0.64	D;D;.
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.52	D
LIST_S2	Uncertain	0.97	.;D;D
M_CAP	Pathogenic	0.68	D
MetaRNN	Benign	0.32	T;T;T
MetaSVM	Benign	-0.69	T
MutationAssessor	Benign	-0.42	N;N;.
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-0.41	N;.;N
REVEL	Uncertain	0.45
Sift	Benign	0.22	T;.;T
Sift4G	Uncertain	0.048	D;D;D
Polyphen		0.24	B;B;.
Vest4		0.23
MutPred		0.56		Loss of MoRF binding (P = 0.0279);Loss of MoRF binding (P = 0.0279);.;
MVP		0.55
MPC		0.76
ClinPred		0.54	D
GERP RS		-6.0
Varity_R		0.34
gMVP		0.52

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: chr12-6976782;