rs80338835

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_ModeratePM2PP5_Very_Strong

The NM_002473.6(MYH9):c.5797C>T(p.Arg1933*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,612,858 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 (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

MYH9
NM_002473.6 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:15O:1

Conservation

PhyloP100: 3.04

Variant links:

Genes affected

MYH9 (HGNC:7579): (myosin heavy chain 9) This gene encodes a conventional non-muscle myosin; this protein should not be confused with the unconventional myosin-9a or 9b (MYO9A or MYO9B). The encoded protein is a myosin IIA heavy chain that contains an IQ domain and a myosin head-like domain which is involved in several important functions, including cytokinesis, cell motility and maintenance of cell shape. Defects in this gene have been associated with non-syndromic sensorineural deafness autosomal dominant type 17, Epstein syndrome, Alport syndrome with macrothrombocytopenia, Sebastian syndrome, Fechtner syndrome and macrothrombocytopenia with progressive sensorineural deafness. [provided by RefSeq, Dec 2011]

MYH9 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0146 CDS is truncated, and there are 3 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 22-36282754-G-A is Pathogenic according to our data. Variant chr22-36282754-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 14072.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-36282754-G-A is described in Lovd as [Pathogenic]. Variant chr22-36282754-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH9	NM_002473.6 link	c.5797C>T	p.Arg1933*	stop_gained	Exon 41 of 41	ENST00000216181.11	NP_002464.1	P35579-1A0A024R1N1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYH9	ENST00000216181.11 link	c.5797C>T	p.Arg1933*	stop_gained	Exon 41 of 41	1	NM_002473.6	ENSP00000216181.6		P35579-1

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152086

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000400

AC:

AN:

249706

Hom.:

AF XY:

0.00000740

AC XY:

AN XY:

135102

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:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000885

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1460772

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

726738

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:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000658

AC:

AN:

152086

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74306

show subpopulations

Gnomad4 AFR

AF:

0.0000242

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:15Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:7

Sep 13, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Identified in more than 40 individuals from over 20 families with variable clinical findings of MYH9-related disease (Sung et al., 2014; Ali et al., 2016; Pecci et al,. 2014; Pecci et al., 2008; Savoia et al., 2010); Published functional studies demonstrate that R1933X does not form organized fibrillar structures with type I collagen and reduces megakaryocyte cell migration (Pecci et al., 2011; Franke et al., 2005); Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 28 amino acids are lost; other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (HGMD); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 10739770, 31064749, 24186861, 23207509, 15339844, 21833445, 19572073, 20694274, 21429376, 10973259, 28880435, 11590545, 10973260, 19954613, 23759689, 27291889, 26226608, 30993846, 33855781, 28983057, 33217855) -

May 03, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP1_strong, PP5, PM2_moderate, PS3, PS4, PVS1_strong -

Aug 05, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The MYH9 c.5797C>T; p.Arg1933Ter variant (rs80338835, ClinVar Variation ID 14072) is reported in the literature in several individuals and families affected with MYH9-related disorders (Ali 2016, Pecci 2008, Safiullina 2022, Seri 2000, Sun 2013, Sung 2014). This variant is only observed on one allele in the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. This variant results in a premature termination codon in the last exon of the MYH9 gene. While this may not lead to nonsense-mediated decay, it is expected to create a truncated protein missing the final 28 amino acids. Functional analyses of the variant protein show disrupted filament assembly and megakaryocyte cell function (Franke 2005, Pecci 2009, Pecci 2011, Safiullina 2022). Additionally, several downstream truncating variants have been described in individuals with MYH9-related disorders and are considered pathogenic (Pecci 2008, Sun 2013). Based on available information, this variant is considered to be pathogenic. References: Ali S et al. Congenital macrothrombocytopenia is a heterogeneous disorder in India. Haemophilia. 2016 Jul;22(4):570-82. PMID: 27291889. Franke JD et al. Rod mutations associated with MYH9-related disorders disrupt nonmuscle myosin-IIA assembly. Blood. 2005 Jan 1;105(1):161-9. PMID: 15339844. Pecci A et al. Position of nonmuscle myosin heavy chain IIA (NMMHC-IIA) mutations predicts the natural history of MYH9-related disease. Hum Mutat. 2008 Mar;29(3):409-17. PMID: 18059020. Pecci A et al. Megakaryocytes of patients with MYH9-related thrombocytopenia present an altered proplatelet formation. Thromb Haemost. 2009 Jul;102(1):90-6. PMID: 19572073. Pecci A et al. Mutations responsible for MYH9-related thrombocytopenia impair SDF-1-driven migration of megakaryoblastic cells. Thromb Haemost. 2011 Oct;106(4):693-704. PMID: 21833445. Safiullina SI et al. A familial case of MYH9 gene mutation associated with multiple functional and structural platelet abnormalities. Sci Rep. 2022 Nov 20;12(1):19975. PMID: 36404341. Seri M et al. Mutations in MYH9 result in the May-Hegglin anomaly, and Fechtner and Sebastian syndromes. The May-Heggllin/Fechtner Syndrome Consortium. Nat Genet. 2000 Sep;26(1):103-5. PMID: 10973259. Sun XH et al. Clinical, pathological, and genetic analysis of ten patients with MYH9-related disease. Acta Haematol. 2013;129(2):106-13. PMID: 23207509. Sung CC et al. R1933X mutation in the MYH9 gene in May-Hegglin anomaly mimicking idiopathic thrombocytopenic purpura. J Formos Med Assoc. 2014 Jan;113(1):56-9. PMID: 23759689. Gene statement: Pathogenic variants in MYH9 are associated with autosomal dominant deafness 17 (MIM: 603622) and autosomal dominant macrothrombocytopenia/granulocyte inclusions with or without nephritis or sensorineural hearing loss (MIM: 155100). -

Oct 13, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Arg1933*) in the MYH9 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 28 amino acid(s) of the MYH9 protein. This variant is present in population databases (rs80338835, gnomAD 0.0009%). This premature translational stop signal has been observed in individuals with MYH9-related disorders (PMID: 10739770, 10973259, 23207509). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 14072). For these reasons, this variant has been classified as Pathogenic. -

Oct 23, 2020

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 08, 2021

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 01, 2021

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Macrothrombocytopenia and granulocyte inclusions with or without nephritis or sensorineural hearing loss

Pathogenic:5Other:1

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

Thrombocytopenia usually remains only disease manifestation throughout life -

Suma Genomics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 01, 2001

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jun 24, 2022

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative or loss of function are potential mechanisms of disease in this gene and are associated with deafness, autosomal dominant 17 (MIM#603622), and macrothrombocytopenia and granulocyte inclusions with or without nephritis or sensorineural hearing loss (MIM#155100). Although the disease mechanism is not well understood, several hypotheses have been proposed including variants that are partially deficient but not complete loss of function, variants that cause various degrees of protein aggregation with deleterious effect, and variants that impair the function of other myosins when copolymerised (PMID: 32545517). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity with regard to age of onset, severity of sensorineural deafness, and the presence or absence of glomerular nephropathy, presenile cataract, and alterations of liver enzymes (PMID: 20301740). (I) 0205 - Variant is predicted to result in a truncated protein (premature termination codon is NOT located at least 54 nucleotides upstream of the final exon-exon junction) with less than 1/3 of the protein sequence affected. (SP) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v3) <0.001 for a dominant condition (1 heterozygote, 0 homozygotes). (SP) 0702 - Other downstream truncating variants comparable to the one identified in this case have strong previous evidence for pathogenicity (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been observed in several families with thrombocytopenia (PMIDs: 29090586, 11159552) and classified as pathogenic by five clinical laboratories in ClinVar. (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Dec 01, 2021

Genetics and Molecular Pathology, SA Pathology

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal dominant nonsyndromic hearing loss 17;C5200934:Macrothrombocytopenia and granulocyte inclusions with or without nephritis or sensorineural hearing loss

Pathogenic:1

Jun 06, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Thrombocytopenia;C1458140:Abnormal bleeding

Pathogenic:1

May 01, 2020

Birmingham Platelet Group; University of Birmingham

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

MYH9-related disorder

Pathogenic:1

Dec 12, 2018

NIHR Bioresource Rare Diseases, University of Cambridge

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

PS4, PM2, PM1, PP4 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.50

BayesDel_noAF

Pathogenic

0.49

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Pathogenic

0.80

Eigen_PC

Uncertain

0.66

FATHMM_MKL

Uncertain

0.83

Vest4

0.67

GERP RS

4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

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