rs587777403

Positions:

• chr1-63593672-G-A
• chr1-63593672-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PM5 PP3_Strong

The NM_002633.3(PGM1):​c.184G>A​(p.Asp62Asn) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D62H) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PGM1 NM_002633.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.60

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]

ACMG classification

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 chr1-63593672-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 133288.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, Uncertain_significance=1}.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.969

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PGM1	NM_002633.3	c.184G>A	p.Asp62Asn	missense_variant	1/11	ENST00000371084.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PGM1	ENST00000371084.8	c.184G>A	p.Asp62Asn	missense_variant	1/11	1	NM_002633.3	P1
PGM1	ENST00000650546.1	c.184G>A	p.Asp62Asn	missense_variant	1/12
ITGB3BP	ENST00000478138.1	n.50C>T		non_coding_transcript_exon_variant	1/5	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.17
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.88	D;.
Eigen	Pathogenic	0.96
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Pathogenic	0.86	D
MetaRNN	Pathogenic	0.97	D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	5.3	H;.
MutationTaster	Benign	1.0	D
PROVEAN	Uncertain	-3.7	D;.
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	D;.
Sift4G	Pathogenic	0.0010	D;.
Polyphen		1.0	D;.
Vest4		0.95
MutPred		0.85		Gain of MoRF binding (P = 0.0446);Gain of MoRF binding (P = 0.0446);
MVP		0.98
ClinPred		1.0	D
GERP RS		4.0
Varity_R		0.98

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

Other links and lift over

dbSNP: rs587777403; hg19: chr1-64059343;