chr6-83178680-ACTT-A

Variant names:

• chr6-83178680-ACTT-A
• rs267608259
• NM_015599.3:c.1019_1021delAAG

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PM4_Supporting PP5_Moderate

The NM_015599.3(PGM3):​c.1019_1021delAAG​(p.Glu340del) variant causes a disruptive inframe deletion change. The variant allele was found at a frequency of 0.000000698 in 1,432,524 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: PGM3 NM_015599.3 disruptive_inframe_deletion
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 6.93
• Publications: 5 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: Orphanet, Labcorp Genetics (formerly Invitae), PanelApp Australia, G2P

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_015599.3. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 6-83178680-ACTT-A is Pathogenic according to our data. Variant chr6-83178680-ACTT-A is described in ClinVar as Pathogenic. ClinVar VariationId is 156471.Status of the report is criteria_provided_single_submitter, 1 stars.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PGM3	NM_015599.3	MANE Select	c.1019_1021delAAG	p.Glu340del	disruptive_inframe_deletion	Exon 8 of 13	NP_056414.1
	PGM3	NM_001199917.2		c.1103_1105delAAG	p.Glu368del	disruptive_inframe_deletion	Exon 9 of 14	NP_001186846.1
	PGM3	NM_001367287.1		c.1103_1105delAAG	p.Glu368del	disruptive_inframe_deletion	Exon 9 of 14	NP_001354216.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PGM3	ENST00000513973.6	TSL:1 MANE Select	c.1019_1021delAAG	p.Glu340del	disruptive_inframe_deletion	Exon 8 of 13	ENSP00000424874.1
	PGM3	ENST00000512866.5	TSL:1	c.1019_1021delAAG	p.Glu340del	disruptive_inframe_deletion	Exon 8 of 14	ENSP00000421565.1
	PGM3	ENST00000283977.9	TSL:5	c.776_778delAAG	p.Glu259del	disruptive_inframe_deletion	Exon 7 of 12	ENSP00000283977.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.98e-7 AC: 1 AN: 1432524 Hom.: 0 AF XY: 0.00000140 AC XY: 1 AN XY: 714730

African (AFR) AF: 0.00 AC: 0 AN: 32816

American (AMR) AF: 0.00 AC: 0 AN: 44644

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25962

East Asian (EAS) AF: 0.00 AC: 0 AN: 39478

South Asian (SAS) AF: 0.00 AC: 0 AN: 85686

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53188

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5696

European-Non Finnish (NFE) AF: 9.21e-7 AC: 1 AN: 1085616

Other (OTH) AF: 0.00 AC: 0 AN: 59438

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1

Nov 24, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In-frame deletion of 1 amino acid in a non-repeat region; In silico analysis supports a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Also known as E340del; This variant is associated with the following publications: (PMID: 24698316, 28704707)

Hyper-IgE syndrome Pathogenic:1

Centre of Chronic Immunodeficiency, Freiburg University

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Immunodeficiency 23 Pathogenic:1

Nov 22, 2024

3billion

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is observed at an extremely low frequency in the gnomAD v4.1.0 dataset (total allele frequency: <0.001%). Predicted Consequence/Location: Inframe deletion located in a nonrepeat region: predicted to change the length of the protein and disrupt normal protein function. The variant has been reported to co-segregate with the disease in at least one similarly affected relative/individual in the same family or similarly affected unrelated family (PMID: 24698316). The variant has been reported to be associated with PGM3 related disorder (ClinVar ID: VCV000156471 /PMID: 24698316). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		6.9
Mutation Taster		=60/40	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs267608259; hg19: chr6-83888399;