rs121964925

Positions:

chr7-134661775-C-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM5PP3_StrongPP5_Moderate

The NM_001724.5(BPGM):c.268C>T(p.Arg90Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000041 in 1,461,840 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R90H) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

BPGM
NM_001724.5 missense

Scores

Clinical Significance

Pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 6.11

Variant links:

Genes affected

BPGM (HGNC:1093): (bisphosphoglycerate mutase) 2,3-diphosphoglycerate (2,3-DPG) is a small molecule found at high concentrations in red blood cells where it binds to and decreases the oxygen affinity of hemoglobin. This gene encodes a multifunctional enzyme that catalyzes 2,3-DPG synthesis via its synthetase activity, and 2,3-DPG degradation via its phosphatase activity. The enzyme also has phosphoglycerate phosphomutase activity. Deficiency of this enzyme increases the affinity of cells for oxygen. Mutations in this gene result in hemolytic anemia. Multiple alternatively spliced variants, encoding the same protein, have been identified. [provided by RefSeq, Sep 2009]

BPGM links:

LOC124901750 (HGNC:):

LOC124901750 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PM1

In a chain Bisphosphoglycerate mutase (size 257) in uniprot entity PMGE_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_001724.5

PM5

Other missense variant is known to change same aminoacid residue: Variant chr7-134661776-G-A is described in Lovd as [Pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.985

PP5

Variant 7-134661775-C-T is Pathogenic according to our data. Variant chr7-134661775-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 12091.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr7-134661775-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BPGM	NM_001724.5 linkuse as main transcript	c.268C>T	p.Arg90Cys	missense_variant	2/3	ENST00000344924.8	NP_001715.1
LOC124901750	XR_007060537.1 linkuse as main transcript	n.29222-41827G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
BPGM	ENST00000344924.8 linkuse as main transcript	c.268C>T	p.Arg90Cys	missense_variant	2/3	1	NM_001724.5	ENSP00000342032	P1
BPGM	ENST00000393132.2 linkuse as main transcript	c.268C>T	p.Arg90Cys	missense_variant	3/4	5		ENSP00000376840	P1
BPGM	ENST00000418040.5 linkuse as main transcript	c.268C>T	p.Arg90Cys	missense_variant	3/4	5		ENSP00000399838	P1
BPGM	ENST00000443095.1 linkuse as main transcript			downstream_gene_variant		4		ENSP00000403050

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000797

AC:

AN:

251036

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135652

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000463

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000410

AC:

AN:

1461840

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727226

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:

0.00

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000936

Hom.:

Bravo

AF:

0.0000151

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Deficiency of bisphosphoglycerate mutase

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 15, 1992

- -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Apr 12, 2023

For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt BPGM protein function. ClinVar contains an entry for this variant (Variation ID: 12091). This variant is also known as Arg89Cys. This missense change has been observed in individual(s) with clinical features of familial erythrocytosis (PMID: 1421379). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs121964925, gnomAD 0.006%). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 90 of the BPGM protein (p.Arg90Cys). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.82

BayesDel_addAF

Pathogenic

0.28

BayesDel_noAF

Pathogenic

0.34

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.54

D;D;D

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.93

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.93

.;.;D

M_CAP

Uncertain

0.19

MetaRNN

Pathogenic

0.99

D;D;D

MetaSVM

Uncertain

0.66

MutationAssessor

Pathogenic

4.3

H;H;H

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Pathogenic

0.82

PROVEAN

Pathogenic

-7.9

D;D;D

REVEL

Pathogenic

0.83

Sift

Pathogenic

0.0

D;D;D

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

1.0

D;D;D

Vest4

0.96

MutPred

0.93

Loss of MoRF binding (P = 0.018);Loss of MoRF binding (P = 0.018);Loss of MoRF binding (P = 0.018);

MVP

0.99

MPC

0.72

ClinPred

1.0

GERP RS

5.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.99

gMVP

0.96

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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