7-134661776-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM5PP3_StrongPP5

The NM_001724.5(BPGM):c.269G>A(p.Arg90His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000991 in 1,614,010 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R90C) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000096 ( 0 hom. )

Consequence

BPGM
NM_001724.5 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 9.94

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 Likely_pathogenic. Variant got 9 ACMG points.

PM1

In a binding_site (size 3) 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 chr7-134661775-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 12091.Status of the report is criteria_provided_single_submitter, 1 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.965

PP5

Variant 7-134661776-G-A is Pathogenic according to our data. Variant chr7-134661776-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 973178.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr7-134661776-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BPGM	NM_001724.5 linkuse as main transcript	c.269G>A	p.Arg90His	missense_variant	2/3	ENST00000344924.8
LOC124901750	XR_007060537.1 linkuse as main transcript	n.29222-41828C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
BPGM	ENST00000344924.8 linkuse as main transcript	c.269G>A	p.Arg90His	missense_variant	2/3	1	NM_001724.5	P1
BPGM	ENST00000393132.2 linkuse as main transcript	c.269G>A	p.Arg90His	missense_variant	3/4	5		P1
BPGM	ENST00000418040.5 linkuse as main transcript	c.269G>A	p.Arg90His	missense_variant	3/4	5		P1
BPGM	ENST00000443095.1 linkuse as main transcript			downstream_gene_variant		4

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152164

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000797

AC:

AN:

251026

Hom.:

AF XY:

0.00000737

AC XY:

AN XY:

135640

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:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000881

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000958

AC:

AN:

1461846

Hom.:

Cov.:

AF XY:

0.0000124

AC XY:

AN XY:

727220

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000989

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152164

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74348

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000282

Hom.:

Bravo

AF:

0.0000189

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Deficiency of bisphosphoglycerate mutase

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 15, 1992

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.89

BayesDel_addAF

Pathogenic

0.35

BayesDel_noAF

Pathogenic

0.37

Cadd

Pathogenic

Dann

Pathogenic

1.0

DEOGEN2

Uncertain

0.56

D;D;D

Eigen

Pathogenic

1.2

Eigen_PC

Pathogenic

1.1

FATHMM_MKL

Pathogenic

0.99

M_CAP

Pathogenic

0.45

MetaRNN

Pathogenic

0.96

D;D;D

MetaSVM

Uncertain

0.74

MutationAssessor

Pathogenic

4.4

H;H;H

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Pathogenic

0.79

PROVEAN

Pathogenic

-4.9

D;D;D

REVEL

Pathogenic

0.92

Sift

Pathogenic

0.0

D;D;D

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

1.0

D;D;D

Vest4

0.95

MutPred

0.82

Loss of MoRF binding (P = 0.0278);Loss of MoRF binding (P = 0.0278);Loss of MoRF binding (P = 0.0278);

MVP

0.95

MPC

1.2

ClinPred

1.0

GERP RS

6.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.96

gMVP

0.94

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