rs6676290

Variant names:

• chr1-63654368-G-A
• rs6676290
• NM_002633.3:c.1501G>A

Your query was ambiguous. Multiple possible variants found:

• chr1-63654368-G-A
• chr1-63654368-G-C

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BA1

The NM_002633.3(PGM1):​c.1501G>A​(p.Val501Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00876 in 1,613,858 control chromosomes in the GnomAD database, including 1,051 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.046 (563 hom., cov: 32)
  • Exomes 𝑓: 0.0048 (488 hom.)
• Consequence: PGM1 NM_002633.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 5.30
• Publications: 10 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: G2P, Orphanet, Genomics England PanelApp, Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 5 uncertain in NM_002633.3
• BP4: Computational evidence support a benign effect (MetaRNN=0.0012457967).
• BP6: Variant 1-63654368-G-A is Benign according to our data. Variant chr1-63654368-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 297892.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.159 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PGM1	NM_002633.3	MANE Select	c.1501G>A	p.Val501Ile	missense	Exon 10 of 11	NP_002624.2
	PGM1	NM_001172818.1		c.1555G>A	p.Val519Ile	missense	Exon 10 of 11	NP_001166289.1	P36871-2
	PGM1	NM_001172819.2		c.910G>A	p.Val304Ile	missense	Exon 10 of 11	NP_001166290.1	P36871-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PGM1	ENST00000371084.8	TSL:1 MANE Select	c.1501G>A	p.Val501Ile	missense	Exon 10 of 11	ENSP00000360125.3	P36871-1
	PGM1	ENST00000895883.1		c.1597G>A	p.Val533Ile	missense	Exon 11 of 12	ENSP00000565942.1
	PGM1	ENST00000650546.1		c.1501G>A	p.Val501Ile	missense	Exon 10 of 12	ENSP00000497812.1	A0A3B3ITK7

Frequencies

GnomAD3 genomes AF: 0.0461 AC: 7015 AN: 152112 Hom.: 558 Cov.: 32

Gnomad AFR AF: 0.162

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0144

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000412

Gnomad OTH AF: 0.0306

GnomAD2 exomes AF: 0.0122 AC: 3062 AN: 251194 AF XY: 0.00901

Gnomad AFR exome AF: 0.164

Gnomad AMR exome AF: 0.00807

Gnomad ASJ exome AF: 0.00328

Gnomad EAS exome AF: 0.0000545

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000423

Gnomad OTH exome AF: 0.00490

GnomAD4 exome AF: 0.00484 AC: 7075 AN: 1461630 Hom.: 488 Cov.: 32 AF XY: 0.00427 AC XY: 3103 AN XY: 727128

African (AFR) AF: 0.164 AC: 5501 AN: 33474

American (AMR) AF: 0.00888 AC: 397 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00379 AC: 99 AN: 26126

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39694

South Asian (SAS) AF: 0.000371 AC: 32 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53408

Middle Eastern (MID) AF: 0.00936 AC: 54 AN: 5768

European-Non Finnish (NFE) AF: 0.000321 AC: 357 AN: 1111810

Other (OTH) AF: 0.0105 AC: 634 AN: 60378

GnomAD4 genome AF: 0.0464 AC: 7056 AN: 152228 Hom.: 563 Cov.: 32 AF XY: 0.0449 AC XY: 3341 AN XY: 74442

African (AFR) AF: 0.162 AC: 6730 AN: 41518

American (AMR) AF: 0.0144 AC: 220 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00288 AC: 10 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.000622 AC: 3 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000412 AC: 28 AN: 68016

Other (OTH) AF: 0.0303 AC: 64 AN: 2114

Alfa AF: 0.0159 Hom.: 549

Bravo AF: 0.0515

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.147 AC: 647

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.0152 AC: 1840

Asia WGS AF: 0.0130 AC: 46 AN: 3478

EpiCase AF: 0.000927

EpiControl AF: 0.000652

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	19
DANN	Benign	0.79
DEOGEN2	Benign	0.36	T
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.39
FATHMM_MKL	Benign	0.30	N
LIST_S2	Benign	0.69	T
MetaRNN	Benign	0.0012	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.26	N
PhyloP100		5.3
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	0.24	N
REVEL	Benign	0.055
Sift	Benign	0.84	T
Sift4G	Benign	0.67	T
Polyphen		0.0070	B
Vest4		0.070
MPC		0.14
ClinPred		0.015	T
GERP RS		4.3
Varity_R		0.098
gMVP		0.23
Mutation Taster		=96/4	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: rs6676290; hg19: chr1-64120039;