chr22-36292060-C-T

Position:

• chr22-36292060-C-T

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM2 PM5 PP2 PP3_Strong PP5_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
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:13 O:1
• Conservation: PhyloP100: 7.90

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 (HGNC:):

ACMG classification

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 gene, where missense usually causes diseases (based on misZ statistic), MYH9. . Gene score misZ 3.473 (greater than the threshold 3.09). Trascript score misZ 6.1231 (greater than threshold 3.09). GenCC has associacion of gene with 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/exons	MANE	Protein	UniProt
MYH9	NM_002473.6	c.4270G>A	p.Asp1424Asn	missense_variant	31/41	ENST00000216181.11	NP_002464.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYH9	ENST00000216181.11	c.4270G>A	p.Asp1424Asn	missense_variant	31/41	1	NM_002473.6	ENSP00000216181.6
MYH9	ENST00000685801.1	c.4333G>A	p.Asp1445Asn	missense_variant	32/42			ENSP00000510688.1
MYH9	ENST00000691109.1	n.4565G>A		non_coding_transcript_exon_variant	25/35

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:13 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Macrothrombocytopenia and granulocyte inclusions with or without nephritis or sensorineural hearing loss Pathogenic:5 Other:1

not provided, no classification provided	literature only	GeneReviews	-	Associated with thrombocytopenia, but low risk of developing other disease manifestations over time -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 15, 2003	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 17, 2023	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. -
Pathogenic, criteria provided, single submitter	clinical testing	ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Suma Genomics	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Dec 29, 2016	- -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Sep 18, 2024	PP1_moderate, PP3, PP5, PM2_moderate, PM5, PS3, PS4 -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 25, 2024	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) -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 11, 2023	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). Advanced 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 at Invitae 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. -

MYH9-related disorder Pathogenic:2

Pathogenic, criteria provided, single submitter	research	NIHR Bioresource Rare Diseases, University of Cambridge	Dec 12, 2018	PS4, PP1_strong, PM2, PP4, PP3 -
Pathogenic, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Aug 18, 2023	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. -

Autosomal dominant nonsyndromic hearing loss 17 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Genetics and Molecular Pathology, SA Pathology

May 31, 2021

- -

Autosomal dominant nonsyndromic hearing loss 17;C5200934:Macrothrombocytopenia and granulocyte inclusions with or without nephritis or sensorineural hearing loss Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Mar 08, 2024

- -

Thrombocytopenia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

MNM Diagnostics

May 27, 2020

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	D
BayesDel_noAF	Benign	-0.10
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.79	D
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.85	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Pathogenic	0.91	D
MutationAssessor	Pathogenic	4.1	H
PrimateAI	Uncertain	0.69	T
PROVEAN	Pathogenic	-4.4	D
REVEL	Pathogenic	0.81
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.011	D
Polyphen		1.0	D
Vest4		0.91
MutPred		0.81		Loss of loop (P = 0.1258);
MVP		0.94
MPC		1.4
ClinPred		1.0	D
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

Other links and lift over

dbSNP: rs80338831; hg19: chr22-36688106; COSMIC: COSV53390646; COSMIC: COSV53390646;