NM_002633.3:c.73C>T

Variant summary

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

The NM_002633.3(PGM1):​c.73C>T​(p.Arg25Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,520 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R25Q) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

PGM1
NM_002633.3 missense

Scores

10
5
3

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.280
Variant links:
Genes affected
PGM1 (HGNC:8905): (phosphoglucomutase 1) The protein encoded by this gene is an isozyme of phosphoglucomutase (PGM) and belongs to the phosphohexose mutase family. There are several PGM isozymes, which are encoded by different genes and catalyze the transfer of phosphate between the 1 and 6 positions of glucose. In most cell types, this PGM isozyme is predominant, representing about 90% of total PGM activity. In red cells, PGM2 is a major isozyme. This gene is highly polymorphic. Mutations in this gene cause glycogen storage disease type 14. Alternativley spliced transcript variants encoding different isoforms have been identified in this gene.[provided by RefSeq, Mar 2010]
ITGB3BP (HGNC:6157): (integrin subunit beta 3 binding protein) This gene encodes a transcriptional coregulator that binds to and enhances the activity of members of the nuclear receptor families, thyroid hormone receptors and retinoid X receptors. This protein also acts as a corepressor of NF-kappaB-dependent signaling. This protein induces apoptosis in breast cancer cells through a caspase 2-mediated signaling pathway. This protein is also a component of the centromere-specific histone H3 variant nucleosome associated complex (CENP-NAC) and may be involved in mitotic progression by recruiting the histone H3 variant CENP-A to the centromere. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Sep 2011]

Genome browser will be placed here

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, 0.755

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PGM1NM_002633.3 linkc.73C>T p.Arg25Trp missense_variant Exon 1 of 11 ENST00000371084.8 NP_002624.2 P36871-1
PGM1NM_001172819.2 linkc.-929C>T upstream_gene_variant NP_001166290.1 P36871-3B4DDQ8

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PGM1ENST00000371084.8 linkc.73C>T p.Arg25Trp missense_variant Exon 1 of 11 1 NM_002633.3 ENSP00000360125.3 P36871-1
PGM1ENST00000650546.1 linkc.73C>T p.Arg25Trp missense_variant Exon 1 of 12 ENSP00000497812.1 A0A3B3ITK7
ITGB3BPENST00000478138.1 linkn.161G>A non_coding_transcript_exon_variant Exon 1 of 5 3
PGM1ENST00000540265.5 linkc.-929C>T upstream_gene_variant 2 ENSP00000443449.1 P36871-3

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000401
AC:
1
AN:
249626
Hom.:
0
AF XY:
0.00000739
AC XY:
1
AN XY:
135370
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000889
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000274
AC:
4
AN:
1461520
Hom.:
0
Cov.:
30
AF XY:
0.00000138
AC XY:
1
AN XY:
727086
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000360
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
Bravo
AF:
0.00000756
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.00000824
AC:
1

ClinVar

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

Submissions by phenotype

Inborn genetic diseases Uncertain:1
Jan 19, 2025
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.73C>T (p.R25W) alteration is located in exon 1 (coding exon 1) of the PGM1 gene. This alteration results from a C to T substitution at nucleotide position 73, causing the arginine (R) at amino acid position 25 to be replaced by a tryptophan (W). 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
0.74
BayesDel_addAF
Pathogenic
0.31
D
BayesDel_noAF
Pathogenic
0.20
CADD
Pathogenic
26
DANN
Pathogenic
1.0
DEOGEN2
Pathogenic
0.86
D;.
Eigen
Uncertain
0.35
Eigen_PC
Uncertain
0.25
FATHMM_MKL
Benign
0.44
N
LIST_S2
Pathogenic
0.99
D;D
M_CAP
Pathogenic
0.36
D
MetaRNN
Pathogenic
0.75
D;D
MetaSVM
Benign
-0.38
T
MutationAssessor
Pathogenic
3.3
M;.
PROVEAN
Uncertain
-2.5
N;.
REVEL
Uncertain
0.48
Sift
Uncertain
0.0010
D;.
Sift4G
Pathogenic
0.0010
D;.
Polyphen
0.97
D;.
Vest4
0.71
MVP
0.84
ClinPred
0.97
D
GERP RS
3.2
Varity_R
0.84

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: rs369296392; hg19: chr1-64059232; API