chr15-72202487-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_002654.6(PKM):​c.1274G>T​(p.Ser425Ile) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Consequence

PKM
NM_002654.6 missense

Scores

8
6
4

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.18
Variant links:
Genes affected
PKM (HGNC:9021): (pyruvate kinase M1/2) This gene encodes a protein involved in glycolysis. The encoded protein is a pyruvate kinase that catalyzes the transfer of a phosphoryl group from phosphoenolpyruvate to ADP, generating ATP and pyruvate. This protein has been shown to interact with thyroid hormone and may mediate cellular metabolic effects induced by thyroid hormones. This protein has been found to bind Opa protein, a bacterial outer membrane protein involved in gonococcal adherence to and invasion of human cells, suggesting a role of this protein in bacterial pathogenesis. Several alternatively spliced transcript variants encoding a few distinct isoforms have been reported. [provided by RefSeq, May 2011]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.769

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PKMNM_002654.6 linkc.1274G>T p.Ser425Ile missense_variant Exon 9 of 11 ENST00000335181.10 NP_002645.3 P14618-1V9HWB8

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PKMENST00000335181.10 linkc.1274G>T p.Ser425Ile missense_variant Exon 9 of 11 1 NM_002654.6 ENSP00000334983.5 P14618-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
33
Bravo
AF:
0.00000378

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Jan 31, 2025
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.1274G>T (p.S425I) alteration is located in exon 9 (coding exon 8) of the PKM gene. This alteration results from a G to T substitution at nucleotide position 1274, causing the serine (S) at amino acid position 425 to be replaced by an isoleucine (I). 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
Pathogenic
0.82
BayesDel_addAF
Pathogenic
0.31
D
BayesDel_noAF
Pathogenic
0.21
CADD
Uncertain
25
DANN
Uncertain
0.99
DEOGEN2
Pathogenic
0.85
.;.;D
Eigen
Benign
0.0084
Eigen_PC
Benign
0.20
FATHMM_MKL
Uncertain
0.94
D
LIST_S2
Uncertain
0.93
D;D;D
M_CAP
Uncertain
0.13
D
MetaRNN
Pathogenic
0.77
D;D;D
MetaSVM
Pathogenic
0.83
D
MutationAssessor
Benign
0.35
.;.;N
PROVEAN
Uncertain
-2.5
N;.;D
REVEL
Pathogenic
0.70
Sift
Pathogenic
0.0
D;.;D
Sift4G
Uncertain
0.016
D;D;D
Polyphen
0.011, 0.014
.;B;B
Vest4
0.66
MutPred
0.72
.;.;Gain of ubiquitination at K422 (P = 0.1062);
MVP
0.93
ClinPred
0.43
T
GERP RS
5.2
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.9
Varity_R
0.74

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs2081968596; hg19: chr15-72494828; API