9-68387471-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_021965.4(PGM5):c.580G>C(p.Val194Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,458,324 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: PGM5 NM_021965.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.07

Genes affected

PGM5 (HGNC:8908): (phosphoglucomutase 5) Phosphoglucomutases (EC 5.2.2.2.), such as PGM5, are phosphotransferases involved in interconversion of glucose-1-phosphate and glucose-6-phosphate. PGM activity is essential in formation of carbohydrates from glucose-6-phosphate and in formation of glucose-6-phosphate from galactose and glycogen (Edwards et al., 1995 [PubMed 8586438]).[supplied by OMIM, Mar 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PGM5	NM_021965.4	c.580G>C	p.Val194Leu	missense_variant	4/11	ENST00000396396.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PGM5	ENST00000396396.6	c.580G>C	p.Val194Leu	missense_variant	4/11	2	NM_021965.4	P1
PGM5	ENST00000396392.5	c.580G>C	p.Val194Leu	missense_variant	4/8	1
PGM5	ENST00000431583.1	c.331G>C	p.Val111Leu	missense_variant	3/4	5
PGM5	ENST00000604870.6	n.935G>C		non_coding_transcript_exon_variant	7/12	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1458324 Hom.: 0 Cov.: 31 AF XY: 0.00000276 AC XY: 2 AN XY: 725624

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00000180

Gnomad4 OTH exome AF: 0.0000332

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 08, 2023

The c.580G>C (p.V194L) alteration is located in exon 4 (coding exon 4) of the PGM5 gene. This alteration results from a G to C substitution at nucleotide position 580, causing the valine (V) at amino acid position 194 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Benign	-0.0064	T
BayesDel_noAF	Benign	-0.25
Cadd	Uncertain	25
Dann	Benign	0.76
Eigen	Benign	0.0073
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.99	D;D;D
M_CAP	Benign	0.020	T
MetaRNN	Uncertain	0.51	D;D;D
MetaSVM	Benign	-0.87	T
MutationAssessor	Uncertain	2.3	M;M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-1.8	N;N;N
REVEL	Benign	0.12
Sift	Uncertain	0.018	D;D;D
Sift4G	Uncertain	0.017	D;D;D
Polyphen		0.091	.;B;.
Vest4		0.64
MutPred		0.61		Loss of helix (P = 0.3949);Loss of helix (P = 0.3949);.;
MVP		0.34
MPC		0.24
ClinPred		0.94	D
GERP RS		5.2
Varity_R		0.22
gMVP		0.69

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: rs782797079; hg19: chr9-71002387;