chr12-6869369-G-C

Position:

• chr12-6869369-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_000365.6(TPI1):​c.436G>C​(p.Glu146Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TPI1 NM_000365.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.03

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 4 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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TPI1	NM_000365.6	c.436G>C	p.Glu146Gln	missense_variant	4/7	ENST00000396705.10	NP_000356.1
TPI1	NM_001159287.1	c.547G>C	p.Glu183Gln	missense_variant	4/7		NP_001152759.1
TPI1	NM_001258026.2	c.190G>C	p.Glu64Gln	missense_variant	4/7		NP_001244955.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TPI1	ENST00000396705.10	c.436G>C	p.Glu146Gln	missense_variant	4/7	1	NM_000365.6	ENSP00000379933	P1

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
AlphaMissense	Benign	0.094
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.060
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.65	D;D;.;.;.;.;T
Eigen	Benign	-0.0018
Eigen_PC	Benign	0.17
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.86	.;D;D;.;D;D;D
M_CAP	Benign	0.026	D
MetaRNN	Uncertain	0.55	D;D;D;D;D;D;D
MetaSVM	Uncertain	0.14	D
MutationAssessor	Benign	0.84	L;L;.;.;.;.;.
MutationTaster	Benign	0.99	D;D;D
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	0.080	N;.;N;.;N;.;.
REVEL	Uncertain	0.34
Sift	Benign	0.24	T;.;T;.;T;.;.
Sift4G	Benign	0.19	T;T;T;T;T;T;T
Polyphen		0.010	B;B;.;.;.;.;.
Vest4		0.48
MutPred		0.63		Gain of MoRF binding (P = 0.049);Gain of MoRF binding (P = 0.049);.;.;.;.;.;
MVP		0.66
MPC		0.39
ClinPred		0.88	D
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.41
gMVP		0.69

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs121964850; hg19: chr12-6978533;