rs727503284

chr22-36289096-C-Achr22-36289096-C-T

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM2 PM5 PP2 PP3_Moderate PP5_Very_Strong

The NM_002473.6(MYH9):c.4546G>T(p.Val1516Leu) 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V1516M) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MYH9 NM_002473.6 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• 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 15 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr22-36289096-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1696214.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, 0.938
• PP5: Variant 22-36289096-C-A is Pathogenic according to our data. Variant chr22-36289096-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 164432.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH9	NM_002473.6	c.4546G>T	p.Val1516Leu	missense_variant	32/41	ENST00000216181.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH9	ENST00000216181.11	c.4546G>T	p.Val1516Leu	missense_variant	32/41	1	NM_002473.6	P1
MYH9	ENST00000685801.1	c.4609G>T	p.Val1537Leu	missense_variant	33/42
MYH9	ENST00000691109.1	n.4841G>T		non_coding_transcript_exon_variant	26/35

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

May 19, 2022

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

May 10, 2021

For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant has been observed in individual(s) with MYH9-related disorders (PMID: 16818291, 24643058). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 164432). This variant is not present in population databases (ExAC no frequency). This sequence change replaces valine with leucine at codon 1516 of the MYH9 protein (p.Val1516Leu). The valine residue is moderately conserved and there is a small physicochemical difference between valine and leucine. -

Rare genetic deafness Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 09, 2017

The p.Val1516Leu variant has been identified in two Chinese individuals with MYH 9 related disease (MYH9-RD), and segregated in 6 affected relatives across the t wo families (Ma 2006, LMM data). This variant has not been reported in large pop ulation studies. The same missense variant resulting from a different DNA change (c.4546G>C, p.Val1516Leu) has also been reported in an individual with MYH9-RD and segregated in 8 affected family members (Zhang 2014). Furthermore, another missense variant at the same amino acid position (p.Val1516Met) has also been id entified in one family with features of MYH9-RD (Pecci 2010, Pecci 2013). In sum mary, this variant meets criteria to be classified as pathogenic for autosomal d ominant MYH9-RD based on the evidence described above. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.83
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.14
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.50	D
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.82	T
M_CAP	Pathogenic	0.37	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Uncertain	0.13	D
MutationAssessor	Pathogenic	3.3	M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-2.0	N
REVEL	Uncertain	0.61
Sift	Benign	0.036	D
Sift4G	Benign	0.33	T
Polyphen		0.62	P
Vest4		0.91
MutPred		0.79		Loss of methylation at K1518 (P = 0.1355);
MVP		0.93
MPC		1.1
ClinPred		0.94	D
GERP RS		5.2
Varity_R		0.28
gMVP		0.57

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs727503284; hg19: chr22-36685142;