MPIG6B

protein-coding

megakaryocyte and platelet inhibitory receptor G6b

Gene summary

This gene is a member of the immunoglobulin (Ig) superfamily and is located in the major histocompatibility complex (MHC) class III region. The protein encoded by this gene is a glycosylated, plasma membrane-bound cell surface receptor, but soluble isoforms encoded by some transcript variants have been found in the endoplasmic reticulum and Golgi before being secreted. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

Previous symbols:

C6orf25

MANE transcript

NM_138272.3

Inheritance

ClinVar variants

P:12U:18B:14

Top phenotype

Thrombocytopenia, anemia, and myelofibrosis

gnomAD constraint

pLI —, LoF o/e 0.86

Max pathogenic AF

—

Genomic locus

chr6:31,718,594-31,726,714

External References & Databases

Ensembl (ENSG00000204420)

Transcript & Mutation Effects

hg38 • Region Span ~8.1 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

thrombocytopenia, anemia, and myelofibrosisSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0044316

Submitter: PanelApp Australia

thrombocytopenia, anemia, and myelofibrosisDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0044316

Submitter: ClinGen

MPIG6B was first reported in relation to autosomal recessive Thrombocytopenia, anemia, and myelofibrosis in 2017 (Melhem et al., 2017; PMID: 27743390). At least 5 unique variants (e.g. missense, splicing, nonsense, and frameshift) have been reported in humans. Evidence supporting this gene disease relationship includes case-level data, segregation data, and experimental data. Variants in this gene have been reported in at least 6 probands in 3 publications (PMIDs: 27743390, 29898956, 31276734). Variants in this gene segregated with disease in 7 additional family members. This gene-disease association is supported by its enhanced expression in lymphoid tissue (PMID: 17311996), its inhibitory biochemical function in platelet activation (PMID: 17311996), and mouse models (including knockout, knock-in, megakaryocyte specific conditional knockout, and humanized models) which recapitulate human disease (PMIDs: 23112346, 23509158, 29891536, 29898956). In summary, MPIG6B is definitively associated with autosomal recessive Thrombocytopenia, anemia, and myelofibrosis.

thrombocytopenia, anemia, and myelofibrosisDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0044316

Submitter: LiferaOmics

ClinGen MPIG6B- related Thrombocytopenia, anemia, and myelofibrosis – Definitive – Approval Date: 10/28/2020 ClinGen Evidence Breakdown Genetic Evidence = 8.5 points Based on: • PMID: 27743390 • PMID: 29898956 • PMID: 31276734 Experimental Evidence = 5.0 points Based on: • PMID: 27743390 – Functional studies demonstrating impaired platelet production and megakaryocyte abnormalities • PMID: 29898956 – Platelet functional assays and mechanistic studies • PMID: 31276734 – Mouse model recapitulating macrothrombocytopenia and myelofibrosis phenotype ClinGen Total = 13.5 Genetic Evidence – Our Cases All three families are unrelated and harbor the same homozygous frameshift variant: Family 1 – one proband. Case-level (biallelic predicted null in AR model; homozygous; consanguinity −0.5 applied) = (1.5 − 0.5) = 1.0; Segregation = 0; Case-control = 0 Family 1 total = 1.0 Family 2 – one proband. Case-level (biallelic predicted null in AR model; homozygous; consanguinity unknown so no deduction applied)= 1.5;Segregation = 0; Case-control = 0 Family 2 total = 1.5 Family 3 – one proband. Case-level (biallelic predicted null in AR model; homozygous; consanguinity −0.5 applied) = (1.5 − 0.5) = 1.0;Segregation = 0; Case-control = 0 Family 3 total = 1.0 Our Cases Total = 3.5 / 12 Updated Total Genetic Evidence (ClinGen + Our Cases) ClinGen genetic evidence: 8.5 Our additional cases: 3.5 Updated genetic total = 12.0 Experimental Evidence (unchanged from ClinGen) ClinGen experimental evidence = 5.0 Updated Overall Score Genetic evidence = 12.0 Experimental evidence = 5.0 Updated total = 17.0

Clinical Genomic Database (CGD)

Thrombocytopenia, anemia, and myelofibrosisAR

Manifestation: Hematologic; Oncologic

Intervention: Hematologic; Oncologic

Rationale: Individuals have been described with myelofibrosis and early-childhood onset thrombocytopenia and anemia, and the use of RBC transfusions have been described (as well as iron and B12/folic acid)

Refs: 27743390

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to MPIG6B variants in ClinVar

9 Conditions Cataloged

not providedTotal: 25

Thrombocytopenia, anemia, and myelofibrosisTotal: 15

MPIG6B-related disorderTotal: 12

not specifiedTotal: 7

ThrombocytopeniaTotal: 2

Abnormal bleedingTotal: 2

Inborn genetic diseasesTotal: 2

C6ORF25 & MPIG6B-related disordersTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_138272.3. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous		1 clinvar	3 clinvar	8 clinvar	1 clinvar	13
missense			15 clinvar	5 clinvar		20
nonsense	3 clinvar	2 clinvar				5
start loss						0
frameshift	2 clinvar	4 clinvar				6
splice donor/acceptor (+/-2bp)						0
Total	5	7	18	13	1	44

Highest pathogenic variant AF is 0.0002534011

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 15 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_138272.3	RefSeq	NP_612116.1	6	MANE Select
ENST00000649779.1	Ensembl	ENSP00000497720.1	6	MANE Select
NM_025260.4	RefSeq	NP_079536.2	6	Standard
NM_138273.3	RefSeq	NP_612117.1	5	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

GPVI-mediated activation cascade
Platelet activation, signaling and aggregation
Hemostasis

Biological Process

integrin-mediated signaling pathway
blood coagulation
negative regulation of signal transduction
platelet activation
erythrocyte differentiation

Molecular Function

protein binding
heparin binding

Cellular Component

endoplasmic reticulum
Golgi apparatus
plasma membrane
integral component of membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000375806
Coding exons: 6
Length: 8121
Individuals with no LoFs: 125702
Homozygous LoFs: 0
Heterozygous LoFs: 44
Defined: 125746
p: 0.000175

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.04	126	163	0.771	0.0000113	1490
Missense (PolyPhen)		41	56.181	0.72978		555
Synonymous	1.65	57	75.1	0.759	0.00000542	560
Loss of Function	0.458	10	11.7	0.855	6.53e-7	110

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00019	0.00012	rare
Latino/Admixed American	0.00012	0.00012	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.0011	0.0011	notable
Finnish	0	0.0	absent
European (Non-Finnish)	0.00016	0.00015	rare
South Asian	0.000033	0.000033	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Inhibitory receptor that acts as a critical regulator of hematopoietic lineage differentiation, megakaryocyte function and platelet production (PubMed:12665801, PubMed:17311996, PubMed:27743390). Inhibits platelet aggregation and activation by agonists such as ADP and collagen-related peptide (PubMed:12665801). This regulation of megakaryocate function as well as platelet production ann activation is done through the inhibition (via the 2 ITIM motifs) of the receptors CLEC1B and GP6:FcRgamma signaling (PubMed:17311996). Appears to operate in a calcium-independent manner (PubMed:12665801). {ECO:0000269|PubMed:12665801, ECO:0000269|PubMed:17311996, ECO:0000269|PubMed:27743390}.;
Disease: DISEASE: Thrombocytopenia, anemia, and myelofibrosis (THAMY) [MIM:617441]: An autosomal recessive disorder characterized by thrombocytopenia, increased number of giant platelets, and anemia manifesting in early childhood. Bone marrow biopsy shows increased number of megakaryocytes and reticular fibrosis consistent with myelofibrosis. {ECO:0000269|PubMed:27743390}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.0690

Intolerance Scores

RVIS EVS: 0.24
RVIS percentile EVS: 69.21

Essentials

Essential (gene trap): N