rs727503284

Variant names:

• chr22-36289096-C-A
• rs727503284
• NM_002473.6:c.4546G>T

Your query was ambiguous. Multiple possible variants found:

• chr22-36289096-C-A
• chr22-36289096-C-T

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM2 PM5 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:4
• Conservation: PhyloP100: 7.90
• Publications: 5 publications found

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 Gene-Disease associations (from GenCC):

• autosomal dominant nonsyndromic hearing loss 17

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• macrothrombocytopenia and granulocyte inclusions with or without nephritis or sensorineural hearing loss

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae), ClinGen
• May-Hegglin anomaly

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• autosomal dominant nonsyndromic hearing loss

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 14 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 VariationId is 1696214.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 VariationId is 164432.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH9	NM_002473.6	c.4546G>T	p.Val1516Leu	missense_variant	Exon 32 of 41	ENST00000216181.11	NP_002464.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYH9	ENST00000216181.11	c.4546G>T	p.Val1516Leu	missense_variant	Exon 32 of 41	1	NM_002473.6	ENSP00000216181.6
MYH9	ENST00000685801.1	c.4609G>T	p.Val1537Leu	missense_variant	Exon 33 of 42			ENSP00000510688.1
MYH9	ENST00000691109.1	n.4841G>T		non_coding_transcript_exon_variant	Exon 26 of 35

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

May 10, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. This variant is not present in population databases (ExAC no frequency). 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). 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"). For these reasons, this variant has been classified as Pathogenic.

Feb 12, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP1_strong, PP2, PM2_moderate, PS1, PS4_moderate

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

May 19, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Rare genetic deafness Pathogenic:1

Mar 09, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
PhyloP100		7.9
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-2.0	N
REVEL	Uncertain	0.61
Sift	Benign	0.036	D
Sift4G	Benign	0.33	T
Vest4		0.91
ClinPred		0.94	D
GERP RS		5.2
Varity_R		0.28
gMVP		0.57
Mutation Taster		=7/93	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs727503284; hg19: chr22-36685142;