9-68387534-G-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Strong BP6_Moderate

The NM_021965.4(PGM5):c.643G>A(p.Gly215Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000393 in 145,022 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00013 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PGM5 NM_021965.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.54

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.017448515).
• BP6: Variant 9-68387534-G-A is Benign according to our data. Variant chr9-68387534-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 2406254.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PGM5	NM_021965.4	c.643G>A	p.Gly215Ser	missense_variant	4/11	ENST00000396396.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PGM5	ENST00000396396.6	c.643G>A	p.Gly215Ser	missense_variant	4/11	2	NM_021965.4	P1
PGM5	ENST00000396392.5	c.643G>A	p.Gly215Ser	missense_variant	4/8	1
PGM5	ENST00000431583.1	c.394G>A	p.Gly132Ser	missense_variant	3/4	5
PGM5	ENST00000604870.6	n.998G>A		non_coding_transcript_exon_variant	7/12	5

Frequencies

GnomAD3 genomes AF: 0.000393 AC: 57 AN: 144906 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000505

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000633

Gnomad ASJ AF: 0.000299

Gnomad EAS AF: 0.00123

Gnomad SAS AF: 0.000219

Gnomad FIN AF: 0.000302

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000261

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000478 AC: 12 AN: 250870 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135578

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.0000618

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000133 AC: 188 AN: 1414160 Hom.: 0 Cov.: 32 AF XY: 0.000135 AC XY: 95 AN XY: 704722

Gnomad4 AFR exome AF: 0.0000927

Gnomad4 AMR exome AF: 0.0000457

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000528

Gnomad4 SAS exome AF: 0.0000824

Gnomad4 FIN exome AF: 0.000152

Gnomad4 NFE exome AF: 0.000119

Gnomad4 OTH exome AF: 0.000342

GnomAD4 genome AF: 0.000393 AC: 57 AN: 145022 Hom.: 0 Cov.: 32 AF XY: 0.000397 AC XY: 28 AN XY: 70594

Gnomad4 AFR AF: 0.000503

Gnomad4 AMR AF: 0.000632

Gnomad4 ASJ AF: 0.000299

Gnomad4 EAS AF: 0.00124

Gnomad4 SAS AF: 0.000220

Gnomad4 FIN AF: 0.000302

Gnomad4 NFE AF: 0.000261

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000847 Hom.: 0

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000659 AC: 8

EpiCase AF: 0.0000546

EpiControl AF: 0.0000593

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 30, 2022

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.39
Cadd	Benign	17
Dann	Benign	0.41
Eigen	Benign	-0.96
Eigen_PC	Benign	-0.72
FATHMM_MKL	Benign	0.27	N
LIST_S2	Benign	0.72	T;T;T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.017	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.84	N;N;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	2.0	N;N;N
REVEL	Benign	0.15
Sift	Benign	1.0	T;T;T
Sift4G	Benign	0.90	T;T;T
Polyphen		0.0	.;B;.
Vest4		0.23
MVP		0.068
MPC		0.23
ClinPred		0.015	T
GERP RS		2.7
Varity_R		0.061
gMVP		0.35

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: rs146547812; hg19: chr9-71002450; COSMIC: COSV67164554;