chr6-83172034-A-C

Variant names:

• chr6-83172034-A-C
• rs1554257039
• NM_015599.3:c.1268T>G

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PM5 PP3_Moderate

The NM_015599.3(PGM3):​c.1268T>G​(p.Met423Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M423T) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PGM3 NM_015599.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.95
• Publications: 0 publications found

Genes affected

PGM3 (HGNC:8907): (phosphoglucomutase 3) This gene encodes a member of the phosphohexose mutase family. The encoded protein mediates both glycogen formation and utilization by catalyzing the interconversion of glucose-1-phosphate and glucose-6-phosphate. A non-synonymous single nucleotide polymorphism in this gene may play a role in resistance to diabetic nephropathy and neuropathy. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Dec 2010]

PGM3 Gene-Disease associations (from GenCC):

• immunodeficiency 23

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Orphanet, ClinGen

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr6-83172034-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 475000.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.884

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015599.3. 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
	PGM3	NM_015599.3	MANE Select	c.1268T>G	p.Met423Arg	missense	Exon 11 of 13	NP_056414.1	O95394-1
	PGM3	NM_001199917.2		c.1352T>G	p.Met451Arg	missense	Exon 12 of 14	NP_001186846.1	O95394-4
	PGM3	NM_001367287.1		c.1352T>G	p.Met451Arg	missense	Exon 12 of 14	NP_001354216.1	O95394-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PGM3	ENST00000513973.6	TSL:1 MANE Select	c.1268T>G	p.Met423Arg	missense	Exon 11 of 13	ENSP00000424874.1	O95394-1
	PGM3	ENST00000512866.5	TSL:1	c.1268T>G	p.Met423Arg	missense	Exon 11 of 14	ENSP00000421565.1	O95394-3
	PGM3	ENST00000283977.9	TSL:5	c.1025T>G	p.Met342Arg	missense	Exon 10 of 12	ENSP00000283977.5	J3KN95

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Immunodeficiency 23 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.23
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.92	D
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Benign	0.073	D
MetaRNN	Pathogenic	0.88	D
MetaSVM	Uncertain	-0.26	T
MutationAssessor	Pathogenic	3.6	H
PhyloP100		8.9
PrimateAI	Uncertain	0.71	T
PROVEAN	Pathogenic	-4.8	D
REVEL	Pathogenic	0.75
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.94
MutPred		0.76		Loss of stability (P = 0.0404)
MVP		0.83
MPC		0.92
ClinPred		1.0	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.94
gMVP		0.99
Mutation Taster		=5/95	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1554257039; hg19: chr6-83881753;