rs77043134

Positions:

• chr1-63623761-G-A
• chr1-63623761-G-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 4P and 16B. PP3_Strong BP6_Very_Strong BS1 BS2

The NM_002633.3(PGM1):​c.247-5664G>A variant causes a intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0125 in 1,602,052 control chromosomes in the GnomAD database, including 156 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.010 (24 hom., cov: 32)
  • Exomes 𝑓: 0.013 (132 hom.)
• Consequence: PGM1 NM_002633.3 intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 9.56

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 Benign. Variant got -12 ACMG points.

• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• BP6: Variant 1-63623761-G-A is Benign according to our data. Variant chr1-63623761-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 445924.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-63623761-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0102 (1552/152262) while in subpopulation NFE AF= 0.0167 (1133/68026). AF 95% confidence interval is 0.0158. There are 24 homozygotes in gnomad4. There are 662 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 24 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PGM1	NM_002633.3	c.247-5664G>A		intron_variant		ENST00000371084.8
PGM1	NM_001172818.1	c.300+1G>A		splice_donor_variant
PGM1	NM_001172819.2	c.-345-5664G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PGM1	ENST00000371084.8	c.247-5664G>A		intron_variant		1	NM_002633.3	P1
PGM1	ENST00000371083.4	c.300+1G>A		splice_donor_variant		2
PGM1	ENST00000540265.5	c.-345-5664G>A		intron_variant		2
PGM1	ENST00000650546.1	c.247-5664G>A		intron_variant

Frequencies

GnomAD3 genomes AF: 0.0102 AC: 1552 AN: 152144 Hom.: 24 Cov.: 32

Gnomad AFR AF: 0.00266

Gnomad AMI AF: 0.104

Gnomad AMR AF: 0.00301

Gnomad ASJ AF: 0.0190

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00434

Gnomad FIN AF: 0.00641

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0167

Gnomad OTH AF: 0.00621

GnomAD3 exomes AF: 0.00931 AC: 2223 AN: 238772 Hom.: 18 AF XY: 0.00950 AC XY: 1246 AN XY: 131174

Gnomad AFR exome AF: 0.00197

Gnomad AMR exome AF: 0.00278

Gnomad ASJ exome AF: 0.0207

Gnomad EAS exome AF: 0.000112

Gnomad SAS exome AF: 0.00253

Gnomad FIN exome AF: 0.00749

Gnomad NFE exome AF: 0.0152

Gnomad OTH exome AF: 0.00864

GnomAD4 exome AF: 0.0128 AC: 18533 AN: 1449790 Hom.: 132 Cov.: 28 AF XY: 0.0126 AC XY: 9119 AN XY: 721556

Gnomad4 AFR exome AF: 0.00211

Gnomad4 AMR exome AF: 0.00326

Gnomad4 ASJ exome AF: 0.0185

Gnomad4 EAS exome AF: 0.0000505

Gnomad4 SAS exome AF: 0.00291

Gnomad4 FIN exome AF: 0.00816

Gnomad4 NFE exome AF: 0.0150

Gnomad4 OTH exome AF: 0.0108

GnomAD4 genome AF: 0.0102 AC: 1552 AN: 152262 Hom.: 24 Cov.: 32 AF XY: 0.00889 AC XY: 662 AN XY: 74456

Gnomad4 AFR AF: 0.00265

Gnomad4 AMR AF: 0.00301

Gnomad4 ASJ AF: 0.0190

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00435

Gnomad4 FIN AF: 0.00641

Gnomad4 NFE AF: 0.0167

Gnomad4 OTH AF: 0.00615

Alfa AF: 0.0145 Hom.: 26

Bravo AF: 0.00931

TwinsUK AF: 0.0167 AC: 62

ALSPAC AF: 0.0130 AC: 50

ESP6500AA AF: 0.00228 AC: 4

ESP6500EA AF: 0.0136 AC: 54

ExAC AF: 0.00981 AC: 1137

Asia WGS AF: 0.00144 AC: 5 AN: 3476

EpiCase AF: 0.0134

EpiControl AF: 0.0122

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 26, 2018	This variant is associated with the following publications: (PMID: 32552793, 28820871, 27124789) -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Sep 01, 2017	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	PGM1: BS1, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

PGM1-congenital disorder of glycosylation Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Aug 16, 2022	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 09, 2023	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.080	D
BayesDel_noAF	Pathogenic	0.36
CADD	Benign	22
DANN	Uncertain	1.0
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
MutationTaster	Benign	1.0	D;D;D
GERP RS		5.0

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
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: rs77043134; hg19: chr1-64089432;