7-44065297-C-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 16P and 5B. PVS1PP5_Very_StrongBS1_SupportingBS2

The NM_000290.4(PGAM2):c.233G>A(p.Trp78Ter) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000383 in 1,613,696 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.0019 ( 2 hom., cov: 33)

Exomes 𝑓: 0.00022 ( 3 hom. )

Consequence

PGAM2
NM_000290.4 stop_gained

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10

Conservation

PhyloP100: 7.68

Variant links:

Genes affected

PGAM2 (HGNC:8889): (phosphoglycerate mutase 2) Phosphoglycerate mutase (PGAM) catalyzes the reversible reaction of 3-phosphoglycerate (3-PGA) to 2-phosphoglycerate (2-PGA) in the glycolytic pathway. The PGAM is a dimeric enzyme containing, in different tissues, different proportions of a slow-migrating muscle (MM) isozyme, a fast-migrating brain (BB) isozyme, and a hybrid form (MB). This gene encodes muscle-specific PGAM subunit. Mutations in this gene cause muscle phosphoglycerate mutase eficiency, also known as glycogen storage disease X. [provided by RefSeq, Sep 2009]

PGAM2 links:

DBNL (HGNC:2696): (drebrin like) Enables cadherin binding activity. Predicted to be involved in several processes, including Rac protein signal transduction; nervous system development; and podosome assembly. Located in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

DBNL links:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PP5

Variant 7-44065297-C-T is Pathogenic according to our data. Variant chr7-44065297-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 418.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4_exome allele frequency = 0.000222 (325/1461362) while in subpopulation AFR AF= 0.00836 (280/33478). AF 95% confidence interval is 0.00756. There are 3 homozygotes in gnomad4_exome. There are 130 alleles in male gnomad4_exome subpopulation. Median coverage is 35. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PGAM2	NM_000290.4 linkuse as main transcript	c.233G>A	p.Trp78Ter	stop_gained	1/3	ENST00000297283.4
DBNL	NM_001014436.3 linkuse as main transcript	c.*4381C>T		3_prime_UTR_variant	13/13	ENST00000448521.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PGAM2	ENST00000297283.4 linkuse as main transcript	c.233G>A	p.Trp78Ter	stop_gained	1/3	1	NM_000290.4	P1
DBNL	ENST00000448521.6 linkuse as main transcript	c.*4381C>T		3_prime_UTR_variant	13/13	1	NM_001014436.3	P4	Q9UJU6-1
	ENST00000445938.1 linkuse as main transcript	n.390C>T		non_coding_transcript_exon_variant	1/2	3

Frequencies

GnomAD3 genomes

AF:

0.00192

AC:

293

AN:

152216

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00683

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000392

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00144

GnomAD3 exomes

AF:

0.000530

AC:

133

AN:

251076

Hom.:

AF XY:

0.000420

AC XY:

AN XY:

135772

show subpopulations

Gnomad AFR exome

AF:

0.00738

Gnomad AMR exome

AF:

0.000202

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:

0.0000176

Gnomad OTH exome

AF:

0.000652

GnomAD4 exome

AF:

0.000222

AC:

325

AN:

1461362

Hom.:

Cov.:

AF XY:

0.000179

AC XY:

130

AN XY:

727020

show subpopulations

Gnomad4 AFR exome

AF:

0.00836

Gnomad4 AMR exome

AF:

0.000246

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:

0.00000450

Gnomad4 OTH exome

AF:

0.000480

GnomAD4 genome

AF:

0.00192

AC:

293

AN:

152334

Hom.:

Cov.:

AF XY:

0.00196

AC XY:

146

AN XY:

74490

show subpopulations

Gnomad4 AFR

AF:

0.00681

Gnomad4 AMR

AF:

0.000392

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.000312

Hom.:

Bravo

AF:

0.00237

ESP6500AA

AF:

0.00908

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000733

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Glycogen storage disease type X

Pathogenic:6

Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	May 09, 2022	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 01, 1993	- -
Pathogenic, criteria provided, single submitter	clinical testing	DASA	Jan 05, 2022	The c.233G>A;p.(Trp78) variant creates a premature translational stop signal in the PGAM2 gene. It is expected to result in an absent or disrupted protein product -PVS1. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (Clinvar ID: 418; PMID: 10545043; 16881065; 18852891; 19783439; 21444020; 23169535; 27612597) - PS4. The p.(Trp78) was detected in trans with a pathogenic variant (PMID: 10545043; 16881065; 19783439; 27612597) - PM3_strong and is allele frequency is greater than expected for disorder - BS1. In summary, the currently available evidence indicates that the variant is pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 11, 2024	This sequence change creates a premature translational stop signal (p.Trp78*) in the PGAM2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PGAM2 are known to be pathogenic (PMID: 8447317, 19273759). This variant is present in population databases (rs10250779, gnomAD 0.7%), and has an allele count higher than expected for a pathogenic variant. This premature translational stop signal has been observed in individuals with phosphoglycerate mutase deficiency (PMID: 8447317, 27612597). ClinVar contains an entry for this variant (Variation ID: 418). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 08, 2023	Variant summary: PGAM2 c.233G>A (p.Trp78X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 0.00053 in 251076 control chromosomes in the gnomAD database, including 1 homozygotes c.233G>A has been reported in the literature in multiple individuals affected with Glycogen Storage Disease Type X (e.g. Tsujino_1993). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, no assertion criteria provided	curation	Reproductive Health Research and Development, BGI Genomics	Jan 06, 2020	NM_000290.3:c.233G>A in the PGAM2 gene has an allele frequency of 0.007 in African subpopulation in the gnomAD database. Koo B et al. found compound heterozygous variants: c.233G>A, and c.278G>A in a patient with Phosphoglycerate mutase deficiency (PMID: 27612597). In addition, Tsujino S et al. found that three patients with phosphoglycerate mutase (PGAM) deficiency were homozygous for this nonsense variant (PMID: 8447317 ). The c.233G>A (p.Trp78*) variant in the PGAM2 gene results in a premature termination codon, predicted to cause a truncated or absent protein due to nonsense mediated decay. Taken together, we interprete this variant as Pathogenic/Likely pathogenic. ACMG/AMP Criteria applied: PVS1; PM3; PP4. -

not provided

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 06, 2022	The most common pathogenic variant identified in patients of African ancestry with PGAM deficiency, likely due to a founder effect (Koo et al., 2016); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 8447317, 23169535, 27612597, 28944235, 19783439, 28492532, 6308514, 2987758, 31589614, 27535533) -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 04, 2020	PVS1, PS4, PP4 -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 29, 2014	- -

PGAM2-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 22, 2023

The PGAM2 c.233G>A variant is predicted to result in premature protein termination (p.Trp78*). This is the most commonly reported causative variant in patients with phosphoglycerate mutase enzyme deficiency (Tsujino et al. 1993. PubMed ID: 8447317; Salameh et al. 2013. PubMed ID: 23169535; Koo and Oskarsson. 2016. PubMed ID: 27612597). This variant has been reported primarily in patients of African descent, which is consistent with the relatively high minor allele frequency in this population in gnomAD. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.26

BayesDel_noAF

Pathogenic

0.57

Cadd

Pathogenic

Dann

Uncertain

1.0

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.91

FATHMM_MKL

Pathogenic

0.99

MutationTaster

Benign

1.0

Vest4

0.27

GERP RS

5.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over