rs140499200

chr6-83188678-T-Achr6-83188678-T-C

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 2P and 7B. PM2 BP4_Moderate BP6 BS1

The NM_015599.3(PGM3):c.325A>T(p.Ile109Phe) variant causes a missense change. The variant allele was found at a frequency of 0.000062 in 1,614,018 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00030 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000038 (0 hom.)
• Consequence: PGM3 NM_015599.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 4.71

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]

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09633973).
• BP6: Variant 6-83188678-T-A is Benign according to our data. Variant chr6-83188678-T-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 541843.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population afr. gnomad4_exome allele frequency = 0.0000376 (55/1461670) while in subpopulation AFR AF= 0.00143 (48/33474). AF 95% confidence interval is 0.00111. There are 0 homozygotes in gnomad4_exome. There are 26 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PGM3	NM_015599.3	c.325A>T	p.Ile109Phe	missense_variant	3/13	ENST00000513973.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PGM3	ENST00000513973.6	c.325A>T	p.Ile109Phe	missense_variant	3/13	1	NM_015599.3	P1

Frequencies

GnomAD3 genomes AF: 0.000296 AC: 45 AN: 152230 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00104

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000915 AC: 23 AN: 251424 Hom.: 0 AF XY: 0.0000662 AC XY: 9 AN XY: 135882

Gnomad AFR exome AF: 0.00117

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000376 AC: 55 AN: 1461670 Hom.: 0 Cov.: 31 AF XY: 0.0000358 AC XY: 26 AN XY: 727154

Gnomad4 AFR exome AF: 0.00143

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000662

GnomAD4 genome AF: 0.000295 AC: 45 AN: 152348 Hom.: 0 Cov.: 32 AF XY: 0.000295 AC XY: 22 AN XY: 74502

Gnomad4 AFR AF: 0.00103

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000868 Hom.: 0

Bravo AF: 0.000314

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000659 AC: 8

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Immunodeficiency 23 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jun 24, 2022

This sequence change replaces isoleucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 137 of the PGM3 protein (p.Ile137Phe). This variant is present in population databases (rs140499200, gnomAD 0.1%). This variant has not been reported in the literature in individuals affected with PGM3-related conditions. ClinVar contains an entry for this variant (Variation ID: 541843). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Nov 09, 2023

Variant summary: PGM3 c.409A>T (p.Ile137Phe) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 9.1e-05 in 251424 control chromosomes, predominantly at a frequency of 0.0012 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 3.39 fold of the estimated maximal expected allele frequency for a pathogenic variant in PGM3 causing Severe Combined Immunodeficiency phenotype (0.00035), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. To our knowledge, no occurrence of c.409A>T in individuals affected with Severe Combined Immunodeficiency and no experimental evidence demonstrating its impact on protein function have been reported. One submitter has cited clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Uncertain	-0.070
Cadd	Benign	23
Dann	Benign	0.97
DEOGEN2	Pathogenic	0.84	D;T;.;.;.;T;.;.
Eigen	Benign	0.18
Eigen_PC	Benign	0.17
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.92	D;D;D;D;D;D;D;D
M_CAP	Benign	0.035	D
MetaRNN	Benign	0.096	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	1.6	L;.;L;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Benign	0.46	T
PROVEAN	Uncertain	-3.9	D;.;D;D;D;D;D;D
REVEL	Benign	0.26
Sift	Benign	0.042	D;.;D;D;D;D;T;T
Sift4G	Uncertain	0.042	D;D;T;D;T;.;.;.
Polyphen		0.98	D;.;.;.;.;.;.;.
Vest4		0.88
MVP		0.74
MPC		0.96
ClinPred		0.20	T
GERP RS		5.8
Varity_R		0.44
gMVP		0.82

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

Publications

LitVar

Other links and lift over

dbSNP: rs140499200; hg19: chr6-83898397;