Genetic Variant PGAM1:p.Ile216Leu (chr10-97432405-A-C) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_002629.4(PGAM1):c.646A>C(p.Ile216Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000354 in 1,611,934 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 29)

Exomes 𝑓: 0.000037 ( 1 hom. )

Consequence

PGAM1
NM_002629.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.19

Variant links:

Genes affected

PGAM1 (HGNC:8888): (phosphoglycerate mutase 1) The protein encoded by this gene is a mutase that catalyzes the reversible reaction of 3-phosphoglycerate (3-PGA) to 2-phosphoglycerate (2-PGA) in the glycolytic pathway. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Nov 2015]

PGAM1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.047822).

BS2

High AC in GnomAdExome4 at 54 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PGAM1	NM_002629.4 link	c.646A>C	p.Ile216Leu	missense_variant	Exon 4 of 4	ENST00000334828.6	NP_002620.1	P18669Q6FHU2
PGAM1	NM_001317079.2 link	c.601A>C	p.Ile201Leu	missense_variant	Exon 4 of 4		NP_001304008.1	Q6FHU2B7Z9E5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PGAM1	ENST00000334828.6 link	c.646A>C	p.Ile216Leu	missense_variant	Exon 4 of 4	1	NM_002629.4	ENSP00000359991.4		P18669
PGAM1	ENST00000467867.1 link	n.902A>C		non_coding_transcript_exon_variant	Exon 4 of 4	2

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152022

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00104

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000676

AC:

AN:

251378

Hom.:

AF XY:

0.000103

AC XY:

AN XY:

135870

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000523

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000370

AC:

AN:

1459796

Hom.:

Cov.:

AF XY:

0.0000578

AC XY:

AN XY:

726204

show subpopulations

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:

0.000592

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000332

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152138

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74362

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000624

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ExAC

AF:

0.0000576

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jun 06, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.646A>C (p.I216L) alteration is located in exon 4 (coding exon 4) of the PGAM1 gene. This alteration results from a A to C substitution at nucleotide position 646, causing the isoleucine (I) at amino acid position 216 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

Benign

0.26

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.13

CADD

Benign

DANN

Benign

0.90

DEOGEN2

Benign

0.30

Eigen

Benign

-0.33

Eigen_PC

Benign

-0.023

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.95

M_CAP

Benign

0.021

MetaRNN

Benign

0.048

MetaSVM

Benign

-0.80

MutationAssessor

Benign

0.70

PrimateAI

Uncertain

0.62

PROVEAN

Benign

0.0

REVEL

Uncertain

0.37

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.36

MutPred

0.55

Gain of glycosylation at T212 (P = 0.2518);

MVP

0.91

MPC

1.0

ClinPred

0.23

GERP RS

5.4

Varity_R

0.23

gMVP

0.59

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over