NM_002633.3:c.343A>C

Variant names:

• chr1-63629521-A-C
• rs121918371
• NM_002633.3:c.343A>C

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2 PM5 PP3_Strong

The NM_002633.3(PGM1):​c.343A>C​(p.Thr115Pro) 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. T115A) 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: 9.20
• Publications: 9 publications found

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]

PGM1 Gene-Disease associations (from GenCC):

• PGM1-congenital disorder of glycosylation

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Ambry Genetics, PanelApp Australia, G2P, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 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 chr1-63629521-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 13650.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.96

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PGM1	NM_002633.3	c.343A>C	p.Thr115Pro	missense_variant	Exon 2 of 11	ENST00000371084.8	NP_002624.2
PGM1	NM_001172818.1	c.397A>C	p.Thr133Pro	missense_variant	Exon 2 of 11		NP_001166289.1
PGM1	NM_001172819.2	c.-249A>C		5_prime_UTR_variant	Exon 2 of 11		NP_001166290.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PGM1	ENST00000371084.8	c.343A>C	p.Thr115Pro	missense_variant	Exon 2 of 11	1	NM_002633.3	ENSP00000360125.3
PGM1	ENST00000650546.1	c.343A>C	p.Thr115Pro	missense_variant	Exon 2 of 12			ENSP00000497812.1
PGM1	ENST00000371083.4	c.397A>C	p.Thr133Pro	missense_variant	Exon 2 of 11	2		ENSP00000360124.4
PGM1	ENST00000540265.5	c.-249A>C		5_prime_UTR_variant	Exon 2 of 11	2		ENSP00000443449.1

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	0.99
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.89	D;.;.
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.99
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;D
M_CAP	Pathogenic	0.30	D
MetaRNN	Pathogenic	0.96	D;D;D
MetaSVM	Pathogenic	0.97	D
MutationAssessor	Pathogenic	4.7	H;.;.
PhyloP100		9.2
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-5.7	D;.;D
REVEL	Pathogenic	0.95
Sift	Uncertain	0.0010	D;.;D
Sift4G	Pathogenic	0.0010	D;.;D
Polyphen		1.0	D;.;D
Vest4		0.86
MutPred		0.85		Gain of disorder (P = 0.0633);Gain of disorder (P = 0.0633);.;
MVP		0.95
MPC		0.81
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.99
gMVP		0.97
Mutation Taster		=5/95	disease causing

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

Other links and lift over

dbSNP: rs121918371; hg19: chr1-64095192;