chr1-63593544-C-G

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2PM5PP3_Strong

The NM_002633.3(PGM1):​c.56C>G​(p.Thr19Arg) variant causes a missense change involving the alteration of a conserved nucleotide. 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T19A) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

PGM1
NM_002633.3 missense

Scores

14
3
1

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.51
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.945

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
PGM1NM_002633.3 linkuse as main transcriptc.56C>G p.Thr19Arg missense_variant 1/11 ENST00000371084.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
PGM1ENST00000371084.8 linkuse as main transcriptc.56C>G p.Thr19Arg missense_variant 1/111 NM_002633.3 P1P36871-1
PGM1ENST00000650546.1 linkuse as main transcriptc.56C>G p.Thr19Arg missense_variant 1/12
ITGB3BPENST00000478138.1 linkuse as main transcriptn.178G>C non_coding_transcript_exon_variant 1/53

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
30
GnomAD4 genome
Cov.:
32

ClinVar

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

Submissions by phenotype

Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsJan 17, 2023The c.56C>G (p.T19R) alteration is located in exon 1 (coding exon 1) of the PGM1 gene. This alteration results from a C to G substitution at nucleotide position 56, causing the threonine (T) at amino acid position 19 to be replaced by an arginine (R). 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
0.99
BayesDel_addAF
Pathogenic
0.41
D
BayesDel_noAF
Pathogenic
0.35
CADD
Pathogenic
31
DANN
Uncertain
0.99
DEOGEN2
Pathogenic
0.87
D;.
Eigen
Pathogenic
0.96
Eigen_PC
Pathogenic
0.80
FATHMM_MKL
Uncertain
0.86
D
LIST_S2
Pathogenic
0.98
D;D
M_CAP
Pathogenic
0.55
D
MetaRNN
Pathogenic
0.95
D;D
MetaSVM
Pathogenic
0.85
D
MutationAssessor
Pathogenic
5.0
H;.
MutationTaster
Benign
1.0
D
PROVEAN
Pathogenic
-4.4
D;.
REVEL
Pathogenic
0.85
Sift
Uncertain
0.0010
D;.
Sift4G
Pathogenic
0.0
D;.
Polyphen
1.0
D;.
Vest4
0.97
MutPred
0.80
Gain of MoRF binding (P = 0.0245);Gain of MoRF binding (P = 0.0245);
MVP
0.95
ClinPred
1.0
D
GERP RS
4.1
Varity_R
0.97

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: chr1-64059215; API