7-134661569-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM1 PP3

The NM_001724.5(BPGM):c.62G>A(p.Arg21His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000353 in 1,614,042 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 Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000033 (0 hom.)
• Consequence: BPGM NM_001724.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 10.0

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]

LOC124901750 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM1: In a chain Bisphosphoglycerate mutase (size 257) in uniprot entity PMGE_HUMAN there are 7 pathogenic changes around while only 1 benign (88%) in NM_001724.5
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.839

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BPGM	NM_001724.5	c.62G>A	p.Arg21His	missense_variant	2/3	ENST00000344924.8
LOC124901750	XR_007060537.1	n.29222-41621C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BPGM	ENST00000344924.8	c.62G>A	p.Arg21His	missense_variant	2/3	1	NM_001724.5	P1
BPGM	ENST00000393132.2	c.62G>A	p.Arg21His	missense_variant	3/4	5		P1
BPGM	ENST00000418040.5	c.62G>A	p.Arg21His	missense_variant	3/4	5		P1
BPGM	ENST00000443095.1	c.62G>A	p.Arg21His	missense_variant	2/2	4

Frequencies

GnomAD3 genomes AF: 0.0000591 AC: 9 AN: 152174 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.0000159 AC: 4 AN: 251394 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135874

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000328 AC: 48 AN: 1461868 Hom.: 0 Cov.: 31 AF XY: 0.0000261 AC XY: 19 AN XY: 727236

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000453

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000216

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome AF: 0.0000591 AC: 9 AN: 152174 Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4 AN XY: 74348

Gnomad4 AFR AF: 0.0000483

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.000100 Hom.: 0

Bravo AF: 0.0000567

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ExAC AF: 0.00000824 AC: 1

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Deficiency of bisphosphoglycerate mutase Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

May 26, 2023

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.41
Cadd	Pathogenic	31
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.59	D;D;D;.
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.84	D;D;D;D
MetaSVM	Pathogenic	0.81	D
MutationAssessor	Pathogenic	4.0	H;H;H;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.72	T
PROVEAN	Uncertain	-3.4	D;D;D;D
REVEL	Pathogenic	0.77
Sift	Uncertain	0.0050	D;D;D;D
Sift4G	Uncertain	0.021	D;D;D;D
Polyphen		1.0	D;D;D;.
Vest4		0.89
MutPred		0.58		Loss of MoRF binding (P = 0.007);Loss of MoRF binding (P = 0.007);Loss of MoRF binding (P = 0.007);Loss of MoRF binding (P = 0.007);
MVP		0.96
MPC		1.1
ClinPred		0.97	D
GERP RS		5.2
Varity_R		0.83
gMVP		0.82

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: rs757985056; hg19: chr7-134346321;