chr1-63654414-T-G

Position:

• chr1-63654414-T-G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP3_Strong

The NM_002633.3(PGM1):​c.1547T>G​(p.Leu516Arg) 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. L516P) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PGM1 NM_002633.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.96

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]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM1: In a strand (size 10) in uniprot entity PGM1_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_002633.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-63654414-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 133286.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.962

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PGM1	NM_002633.3	c.1547T>G	p.Leu516Arg	missense_variant	10/11	ENST00000371084.8
PGM1	NM_001172818.1	c.1601T>G	p.Leu534Arg	missense_variant	10/11
PGM1	NM_001172819.2	c.956T>G	p.Leu319Arg	missense_variant	10/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PGM1	ENST00000371084.8	c.1547T>G	p.Leu516Arg	missense_variant	10/11	1	NM_002633.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.86	D;.;.;.
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;D;D
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.96	D;D;D;D
MetaSVM	Uncertain	-0.011	T
MutationAssessor	Pathogenic	3.9	H;.;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.74	T
PROVEAN	Pathogenic	-4.7	D;.;D;D
REVEL	Pathogenic	0.85
Sift	Pathogenic	0.0	D;.;D;D
Sift4G	Pathogenic	0.0010	D;.;D;D
Polyphen		1.0	D;.;.;D
Vest4		0.94
MutPred		0.85		Loss of stability (P = 0.0126);Loss of stability (P = 0.0126);.;.;
MVP		0.81
MPC		0.86
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.98
gMVP		0.92

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: rs587777401; hg19: chr1-64120085;