rs121964850

Variant names:

• chr12-6869369-G-C
• rs121964850
• NM_000365.6:c.436G>C

Your query was ambiguous. Multiple possible variants found:

• chr12-6869369-G-C
• chr12-6869369-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP2

The ENST00000396705.10(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 ENST00000396705.10 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.03
• Publications: 2 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 3 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: 1.6741 (below the threshold of 3.09). GenCC associations: The gene is linked to triosephosphate isomerase deficiency.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000396705.10. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TPI1	NM_000365.6	MANE Select	c.436G>C	p.Glu146Gln	missense	Exon 4 of 7	NP_000356.1
	TPI1	NM_001159287.1		c.547G>C	p.Glu183Gln	missense	Exon 4 of 7	NP_001152759.1
	TPI1	NM_001258026.2		c.190G>C	p.Glu64Gln	missense	Exon 4 of 7	NP_001244955.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TPI1	ENST00000396705.10	TSL:1 MANE Select	c.436G>C	p.Glu146Gln	missense	Exon 4 of 7	ENSP00000379933.4
	TPI1	ENST00000229270.8	TSL:1	c.547G>C	p.Glu183Gln	missense	Exon 4 of 7	ENSP00000229270.4
	TPI1	ENST00000613953.4	TSL:1	c.547G>C	p.Glu183Gln	missense	Exon 4 of 7	ENSP00000484435.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-0.0018
Eigen_PC	Benign	0.17
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.026	D
MetaRNN	Uncertain	0.55	D
MetaSVM	Uncertain	0.14	D
MutationAssessor	Benign	0.84	L
PhyloP100		8.0
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	0.080	N
REVEL	Uncertain	0.34
Sift	Benign	0.24	T
Sift4G	Benign	0.19	T
Polyphen		0.010	B
Vest4		0.48
MutPred		0.63		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
Mutation Taster		=72/28	polymorphism

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

Other links and lift over

dbSNP: rs121964850; hg19: chr12-6978533;