22-36292060-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM2PM5PP2PP3_StrongPP5_Very_Strong

The NM_002473.6(MYH9):c.4270G>A(p.Asp1424Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D1424H) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

MYH9
NM_002473.6 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:14O:1

Conservation

PhyloP100: 7.90

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 17 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr22-36292060-C-G is described in Lovd as [Pathogenic].

PP2

Missense variant in the MYH9 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 43 curated pathogenic missense variants (we use a threshold of 10). The gene has 84 curated benign missense variants. Gene score misZ: 3.473 (above the threshold of 3.09). Trascript score misZ: 6.1231 (above the threshold of 3.09). GenCC associations: The gene is linked to May-Hegglin anomaly, autosomal dominant nonsyndromic hearing loss, macrothrombocytopenia and granulocyte inclusions with or without nephritis or sensorineural hearing loss, autosomal dominant nonsyndromic hearing loss 17.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.973

PP5

Variant 22-36292060-C-T is Pathogenic according to our data. Variant chr22-36292060-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 14082.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-36292060-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH9	NM_002473.6 link	c.4270G>A	p.Asp1424Asn	missense_variant	Exon 31 of 41	ENST00000216181.11	NP_002464.1	P35579-1A0A024R1N1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
MYH9	ENST00000216181.11 link	c.4270G>A	p.Asp1424Asn	missense_variant	Exon 31 of 41	1	NM_002473.6	ENSP00000216181.6	P35579-1
MYH9	ENST00000685801.1 link	c.4333G>A	p.Asp1445Asn	missense_variant	Exon 32 of 42			ENSP00000510688.1	A0A8I5KWT8
MYH9	ENST00000691109.1 link	n.4565G>A		non_coding_transcript_exon_variant	Exon 25 of 35

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:14Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

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

Associated with thrombocytopenia, but low risk of developing other disease manifestations over time -

Suma Genomics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 15, 2003

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Dec 29, 2016

Genetic Services Laboratory, University of Chicago

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

- -

Nov 17, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: MYH9 c.4270G>A (p.Asp1424Asn) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251372 control chromosomes. c.4270G>A has been reported in the literature in multiple individuals affected with Macrothrombocytopenia And Granulocyte Inclusions With Or Without Nephritis Or Sensorineural Hearing Loss (Deutsch_2003, Verver_2016), and it co-segregated with disease conditions in two large families (Deutsch_2003). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <50% of normal protein levels in patients' cells (Deutsch_2003). The following publications have been ascertained in the context of this evaluation (PMID: 12649151, 26226608). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided

Pathogenic:3

Sep 18, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP1_moderate, PP3, PP5, PM2_moderate, PM5, PS3, PS4 -

Aug 30, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 1424 of the MYH9 protein (p.Asp1424Asn). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with MYH9-related disorders (PMID: 11159552, 23207509). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 14082). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MYH9 protein function. Experimental studies have shown that this missense change affects MYH9 function (PMID: 15339844). For these reasons, this variant has been classified as Pathogenic. -

Jul 25, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a damaging effect on platelet count, platelet size, and bleeding time (PMID: 35584211, 32315395, 21908426); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 30725031, 31064749, 23207509, 22217922, 22967416, 27577209, 26226608, 26942920, 29451856, 32581362, 33855781, 34711033, 34711031, 35295078, 16162639, 24186861, 12649151, 21908426, 32315395, 15339844, 19572073, 35584211, 11159552) -

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

Pathogenic:2

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2_Supporting+PP3_Moderate+PP2+PM5+PP1_Strong+PS4_Supporting -

Mar 08, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

MYH9-related disorder

Pathogenic:2

Aug 18, 2023

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The MYH9 c.4270G>A variant is predicted to result in the amino acid substitution p.Asp1424Asn. This variant has been reported to be causative for MYH9-related disorders in several unrelated families (see for example Kunishima et al. 2001. PubMed ID: 11159552; Seri et al. 2003. PubMed ID: 12792306; Dong et al. 2005. PubMed ID: 16098078; Verver et al. 2016. PubMed ID: 26226608). The c.4270G>A substitution is one of the most common pathogenic variants found in the MYH9 gene, and it is thought to cause disease due to haploinsufficiency from unstable MYH9 protein (Deutsch et al. 2003. PubMed ID: 12649151). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic. -

Dec 12, 2018

NIHR Bioresource Rare Diseases, University of Cambridge

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

PS4, PP1_strong, PM2, PP4, PP3 -

Autosomal dominant nonsyndromic hearing loss 17

Pathogenic:1

May 31, 2021

Genetics and Molecular Pathology, SA Pathology

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Thrombocytopenia

Pathogenic:1

May 27, 2020

MNM Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

According to ACMG Guidelines, the variant meets the following criteria of pathogenicity: PS4, PM2, PM5, PP2, PP3, PP4, PP5. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.60

BayesDel_addAF

Uncertain

0.099

BayesDel_noAF

Benign

-0.10

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.79

Eigen

Pathogenic

0.81

Eigen_PC

Pathogenic

0.71

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.97

M_CAP

Pathogenic

0.85

MetaRNN

Pathogenic

0.97

MetaSVM

Pathogenic

0.91

MutationAssessor

Pathogenic

4.1

PrimateAI

Uncertain

0.69

PROVEAN

Pathogenic

-4.4

REVEL

Pathogenic

0.81

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.011

Polyphen

1.0

Vest4

0.91

MutPred

0.81

Loss of loop (P = 0.1258);

MVP

0.94

MPC

1.4

ClinPred

1.0

GERP RS

4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.2

Varity_R

0.74

gMVP

0.56

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