rs80338830

Positions:

• chr22-36295068-C-A

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2 PM5 PP2 PP3_Strong PP5_Moderate

The NM_002473.6(MYH9):​c.3494G>T​(p.Arg1165Leu) 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. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1165C) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: MYH9 NM_002473.6 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1 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]

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr22-36295069-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 14074.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant where missense usually causes diseases, MYH9
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.955
• PP5: Variant 22-36295068-C-A is Pathogenic according to our data. Variant chr22-36295068-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 38965.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr22-36295068-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH9	NM_002473.6	c.3494G>T	p.Arg1165Leu	missense_variant	27/41	ENST00000216181.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH9	ENST00000216181.11	c.3494G>T	p.Arg1165Leu	missense_variant	27/41	1	NM_002473.6	P1
MYH9	ENST00000685801.1	c.3557G>T	p.Arg1186Leu	missense_variant	28/42
MYH9	ENST00000691109.1	n.3789G>T		non_coding_transcript_exon_variant	21/35

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Jul 17, 2023	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative and loss of function are likely mechanisms of disease in this gene, and are associated with macrothrombocytopenia and granulocyte inclusions with or without nephritis or sensorineural hearing loss (MIM#155100) and autosomal dominant deafness 17 (MIM#603622) (PMIDs: 20301740, 32545517). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity. Expressivity varies for onset and severity of sensorineural deafness, glomerular nephropathy, presenile cataract, and alterations of liver enzymes (PMID: 20301740). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to leucine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated myosin tail 1 (DECIPHER). (I) 0703 - Another missense variant comparable to the one identified in this case has moderate previous evidence for pathogenicity. p.(Arg1165Cys) has been reported as pathogenic by many clinical testing laboratories (ClinVar). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported in at least five unrelated individuals with MYH9-related disease, and hearing loss has also been reported in some of those individuals (PMIDs: 11776386, 26226608, 33217855, 33718801). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
not provided, no classification provided	literature only	GeneReviews	-	Associated with high risk for hearing loss and low risk for nephropathy and cataract -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.39
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.74	D
Eigen	Pathogenic	0.71
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.60	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Uncertain	0.71	D
MutationAssessor	Pathogenic	3.7	H
MutationTaster	Benign	1.0	A
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-6.4	D
REVEL	Pathogenic	0.92
Sift	Uncertain	0.025	D
Sift4G	Uncertain	0.022	D
Polyphen		0.92	P
Vest4		0.91
MutPred		0.76		Loss of methylation at K1164 (P = 0.0343);
MVP		0.94
MPC		1.6
ClinPred		1.0	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.66
gMVP		0.74

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

Publications

LitVar

Other links and lift over

dbSNP: rs80338830; hg19: chr22-36691114;