NM_001724.5:c.289G>A

Variant names:

• chr7-134661796-G-A
• rs1374672280
• NM_001724.5:c.289G>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001724.5(BPGM):​c.289G>A​(p.Gly97Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000123 in 1,461,512 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G97R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: BPGM NM_001724.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.09
• Publications: 3 publications found

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 Gene-Disease associations (from GenCC):

• hemolytic anemia due to diphosphoglycerate mutase deficiency

  Inheritance: AR Classification: STRONG, MODERATE, LIMITED Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics

LOC124901750 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.907

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001724.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BPGM	NM_001724.5	MANE Select	c.289G>A	p.Gly97Ser	missense	Exon 2 of 3	NP_001715.1	P07738
	BPGM	NM_001293085.2		c.289G>A	p.Gly97Ser	missense	Exon 3 of 4	NP_001280014.1	P07738
	BPGM	NM_199186.3		c.289G>A	p.Gly97Ser	missense	Exon 3 of 4	NP_954655.1	A0A024R782

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BPGM	ENST00000344924.8	TSL:1 MANE Select	c.289G>A	p.Gly97Ser	missense	Exon 2 of 3	ENSP00000342032.3	P07738
	BPGM	ENST00000393132.2	TSL:5	c.289G>A	p.Gly97Ser	missense	Exon 3 of 4	ENSP00000376840.2	P07738
	BPGM	ENST00000418040.5	TSL:5	c.289G>A	p.Gly97Ser	missense	Exon 3 of 4	ENSP00000399838.1	P07738

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000160 AC: 4 AN: 250668 AF XY: 0.0000222

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000123 AC: 18 AN: 1461512 Hom.: 0 Cov.: 31 AF XY: 0.0000179 AC XY: 13 AN XY: 727026

African (AFR) AF: 0.0000299 AC: 1 AN: 33450

American (AMR) AF: 0.0000224 AC: 1 AN: 44664

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26100

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39692

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86220

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000989 AC: 11 AN: 1111842

Other (OTH) AF: 0.00 AC: 0 AN: 60368

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000189

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.82
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Pathogenic	0.19
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.58	D
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.91	D
MetaSVM	Uncertain	0.61	D
MutationAssessor	Pathogenic	4.3	H
PhyloP100		8.1
PrimateAI	Uncertain	0.70	T
PROVEAN	Pathogenic	-5.9	D
REVEL	Pathogenic	0.87
Sift	Uncertain	0.013	D
Sift4G	Uncertain	0.0070	D
Polyphen		0.70	P
Vest4		0.57
MutPred		0.92		Gain of MoRF binding (P = 0.0858)
MVP		0.93
MPC		0.84
ClinPred		0.85	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.83
gMVP		0.89
Mutation Taster		=39/61	disease causing

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

Other links and lift over

dbSNP: rs1374672280; hg19: chr7-134346548; COSMIC: COSV61324490; COSMIC: COSV61324490;