Genetic Variant PGM1:c.247-5664G>A (chr1-63623761-G-A) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 8P and 16B. PVS1BP6_Very_StrongBS1BS2

The NM_001172818.1(PGM1):c.300+1G>A variant causes a splice donor, 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. 2/3 splice prediction tools predicting alterations to normal splicing. 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_001172818.1 splice_donor, intron

Scores

Splicing: ADA: 1.000

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 9.56

Publications

6 publications found

Variant links:

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: G2P, Orphanet, Genomics England PanelApp, Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae)

PGM1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.

BP6

Variant 1-63623761-G-A is Benign according to our data. Variant chr1-63623761-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 445924.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 24 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001172818.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
PGM1	NM_002633.3	MANE Select	c.247-5664G>A	intron	N/A	NP_002624.2
PGM1	NM_001172818.1		c.300+1G>A	splice_donor intron	N/A	NP_001166289.1	P36871-2
PGM1	NM_001172819.2		c.-345-5664G>A	intron	N/A	NP_001166290.1	P36871-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
PGM1	ENST00000371084.8	TSL:1 MANE Select	c.247-5664G>A	intron	N/A	ENSP00000360125.3	P36871-1
PGM1	ENST00000895883.1		c.247-5664G>A	intron	N/A	ENSP00000565942.1
PGM1	ENST00000650546.1		c.247-5664G>A	intron	N/A	ENSP00000497812.1	A0A3B3ITK7

Frequencies

GnomAD3 genomes

AF:

0.0102

AC:

1552

AN:

152144

Hom.:

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.00931

AC:

2223

AN:

238772

AF XY:

0.00950

show subpopulations

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 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.:

AF XY:

0.0126

AC XY:

9119

AN XY:

721556

show subpopulations

African (AFR)

AF:

0.00211

AC:

AN:

33216

American (AMR)

AF:

0.00326

AC:

145

AN:

44544

Ashkenazi Jewish (ASJ)

AF:

0.0185

AC:

481

AN:

25938

East Asian (EAS)

AF:

0.0000505

AC:

AN:

39600

South Asian (SAS)

AF:

0.00291

AC:

250

AN:

85882

European-Finnish (FIN)

AF:

0.00816

AC:

423

AN:

51868

Middle Eastern (MID)

AF:

0.00227

AC:

AN:

5734

European-Non Finnish (NFE)

AF:

0.0150

AC:

16501

AN:

1103018

Other (OTH)

AF:

0.0108

AC:

648

AN:

59990

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

845

1690

2536

3381

4226

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

570

1140

1710

2280

2850

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0102

AC:

1552

AN:

152262

Hom.:

Cov.:

AF XY:

0.00889

AC XY:

662

AN XY:

74456

show subpopulations

African (AFR)

AF:

0.00265

AC:

110

AN:

41536

American (AMR)

AF:

0.00301

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.0190

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.00435

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00641

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0167

AC:

1133

AN:

68026

Other (OTH)

AF:

0.00615

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

168

251

335

419

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0142

Hom.:

Bravo

AF:

0.00931

TwinsUK

AF:

0.0167

AC:

ALSPAC

AF:

0.0130

AC:

ESP6500AA

AF:

0.00228

AC:

ESP6500EA

AF:

0.0136

AC:

ExAC

AF:

0.00981

AC:

1137

Asia WGS

AF:

0.00144

AC:

AN:

3476

EpiCase

AF:

0.0134

EpiControl

AF:

0.0122

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (6)

PGM1-congenital disorder of glycosylation (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Uncertain

0.080

BayesDel_noAF

Pathogenic

0.36

CADD

Benign

(source)

DANN

Uncertain

1.0

Eigen

Pathogenic

1.2

Eigen_PC

Pathogenic

1.0

FATHMM_MKL

Pathogenic

0.99

PhyloP100

9.6

GERP RS

5.0

Mutation Taster

=59/41

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over