rs855314

Variant names:

• chr1-63629440-A-G
• rs855314
• NM_002633.3:c.262A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002633.3(PGM1):​c.262A>G​(p.Ile88Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.143 in 1,611,504 control chromosomes in the GnomAD database, including 17,798 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. I88I) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.16 (2331 hom., cov: 32)
  • Exomes 𝑓: 0.14 (15467 hom.)
• Consequence: PGM1 NM_002633.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 9.20
• Publications: 23 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002285391).
• BP6: Variant 1-63629440-A-G is Benign according to our data. Variant chr1-63629440-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 297871.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.241 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002633.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PGM1	NM_002633.3	MANE Select	c.262A>G	p.Ile88Val	missense	Exon 2 of 11	NP_002624.2
	PGM1	NM_001172819.2		c.-330A>G		5_prime_UTR_premature_start_codon_gain	Exon 2 of 11	NP_001166290.1
	PGM1	NM_001172818.1		c.316A>G	p.Ile106Val	missense	Exon 2 of 11	NP_001166289.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PGM1	ENST00000371084.8	TSL:1 MANE Select	c.262A>G	p.Ile88Val	missense	Exon 2 of 11	ENSP00000360125.3
	PGM1	ENST00000540265.5	TSL:2	c.-330A>G		5_prime_UTR_premature_start_codon_gain	Exon 2 of 11	ENSP00000443449.1
	PGM1	ENST00000650546.1		c.262A>G	p.Ile88Val	missense	Exon 2 of 12	ENSP00000497812.1

Frequencies

GnomAD3 genomes AF: 0.163 AC: 24762 AN: 151950 Hom.: 2322 Cov.: 32

Gnomad AFR AF: 0.245

Gnomad AMI AF: 0.147

Gnomad AMR AF: 0.111

Gnomad ASJ AF: 0.137

Gnomad EAS AF: 0.00867

Gnomad SAS AF: 0.0907

Gnomad FIN AF: 0.128

Gnomad MID AF: 0.142

Gnomad NFE AF: 0.148

Gnomad OTH AF: 0.172

GnomAD2 exomes AF: 0.125 AC: 31190 AN: 248928 AF XY: 0.125

Gnomad AFR exome AF: 0.247

Gnomad AMR exome AF: 0.0696

Gnomad ASJ exome AF: 0.131

Gnomad EAS exome AF: 0.00718

Gnomad FIN exome AF: 0.132

Gnomad NFE exome AF: 0.151

Gnomad OTH exome AF: 0.129

GnomAD4 exome AF: 0.140 AC: 204850 AN: 1459436 Hom.: 15467 Cov.: 32 AF XY: 0.139 AC XY: 101033 AN XY: 726132

African (AFR) AF: 0.255 AC: 8519 AN: 33394

American (AMR) AF: 0.0745 AC: 3332 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.133 AC: 3471 AN: 26106

East Asian (EAS) AF: 0.00428 AC: 170 AN: 39692

South Asian (SAS) AF: 0.0986 AC: 8505 AN: 86218

European-Finnish (FIN) AF: 0.130 AC: 6930 AN: 53414

Middle Eastern (MID) AF: 0.191 AC: 1099 AN: 5750

European-Non Finnish (NFE) AF: 0.148 AC: 164358 AN: 1109830

Other (OTH) AF: 0.140 AC: 8466 AN: 60320

GnomAD4 genome AF: 0.163 AC: 24806 AN: 152068 Hom.: 2331 Cov.: 32 AF XY: 0.160 AC XY: 11904 AN XY: 74318

African (AFR) AF: 0.245 AC: 10167 AN: 41460

American (AMR) AF: 0.111 AC: 1692 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.137 AC: 477 AN: 3470

East Asian (EAS) AF: 0.00908 AC: 47 AN: 5178

South Asian (SAS) AF: 0.0908 AC: 437 AN: 4812

European-Finnish (FIN) AF: 0.128 AC: 1358 AN: 10582

Middle Eastern (MID) AF: 0.150 AC: 44 AN: 294

European-Non Finnish (NFE) AF: 0.148 AC: 10092 AN: 67968

Other (OTH) AF: 0.170 AC: 358 AN: 2106

Alfa AF: 0.150 Hom.: 5205

Bravo AF: 0.164

TwinsUK AF: 0.149 AC: 553

ALSPAC AF: 0.147 AC: 567

ESP6500AA AF: 0.240 AC: 1057

ESP6500EA AF: 0.141 AC: 1212

ExAC AF: 0.130 AC: 15834

Asia WGS AF: 0.0700 AC: 245 AN: 3478

EpiCase AF: 0.147

EpiControl AF: 0.151

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	not provided (2)
-	-	2	PGM1-congenital disorder of glycosylation (2)
-	-	1	Congenital disorder of glycosylation (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	19
DANN	Benign	0.97
DEOGEN2	Benign	0.38	T
Eigen	Benign	-0.23
Eigen_PC	Benign	0.044
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
MetaRNN	Benign	0.0023	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.74	N
PhyloP100		9.2
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-0.030	N
REVEL	Benign	0.19
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.11	B
Vest4		0.34
MPC		0.64
ClinPred		0.035	T
GERP RS		5.5
Varity_R		0.14
gMVP		0.55
Mutation Taster		=55/45	polymorphism (auto)

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: rs855314; hg19: chr1-64095111; COSMIC: COSV64300349;