chr22-36284474-C-T

Variant names:

• chr22-36284474-C-T
• rs80338834
• NM_002473.6:c.5521G>A

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PS3 PM2 PP3_Strong PP5_Very_Strong

The NM_002473.6(MYH9):​c.5521G>A​(p.Glu1841Lys) 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 (★★). ClinVar reports functional evidence for this variant: "SCV005203185: The most pronounced variant effect results in partial loss of coiled-coil structure of MYH9 in vitro (Franke_2005). PMID:15339844" and additional evidence is available in ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: MYH9 NM_002473.6 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:15 O:1
• Conservation: PhyloP100: 7.58
• Publications: 68 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: Labcorp Genetics (formerly Invitae), G2P
• macrothrombocytopenia and granulocyte inclusions with or without nephritis or sensorineural hearing loss

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, ClinGen, Labcorp Genetics (formerly Invitae), Orphanet
• 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 18 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV005203185: The most pronounced variant effect results in partial loss of coiled-coil structure of MYH9 in vitro (Franke_2005). PMID: 15339844; SCV003444534: Experimental studies have shown that this missense change affects MYH9 function (PMID: 15339844).; SCV003799906: Functional analyses have shown that the variant protein has altered morphology and function (Cechova 2018, Franke 2005, Pal 2020, Zhang 2012). PMID: 28993503. PMID: 15339844. PMID: 22080149. PMID: 11590545. PMID: 33855781. PMID: 32315395. PMID: 24186861. PMID: 10973259. PMID: 21908426.; SCV003930255: Published functional studies demonstrate the p.(E1841K) variant is sufficient to induce phenotypes observed in MYH9-related disease (Zhang et al., 2012; Cechova et al., 2018)
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.982
• PP5: Variant 22-36284474-C-T is Pathogenic according to our data. Variant chr22-36284474-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 14073.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002473.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH9	NM_002473.6	MANE Select	c.5521G>A	p.Glu1841Lys	missense	Exon 39 of 41	NP_002464.1	P35579-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH9	ENST00000216181.11	TSL:1 MANE Select	c.5521G>A	p.Glu1841Lys	missense	Exon 39 of 41	ENSP00000216181.6	P35579-1
	MYH9	ENST00000685801.1		c.5584G>A	p.Glu1862Lys	missense	Exon 40 of 42	ENSP00000510688.1	A0A8I5KWT8
	MYH9	ENST00000955568.1		c.5584G>A	p.Glu1862Lys	missense	Exon 40 of 42	ENSP00000625627.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
7	-	-	not provided (7)
4	-	-	Macrothrombocytopenia and granulocyte inclusions with or without nephritis or sensorineural hearing loss (5)
2	-	-	MYH9-related disorder (2)
1	-	-	Autosomal dominant nonsyndromic hearing loss 17 (1)
1	-	-	Deafness (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.39
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.73	D
Eigen	Pathogenic	0.74
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.72	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	0.84	D
MutationAssessor	Pathogenic	3.9	H
PhyloP100		7.6
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-3.2	D
REVEL	Pathogenic	0.91
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.92
MutPred		0.83		Gain of methylation at E1841 (P = 0.0159)
MVP		0.92
MPC		1.3
ClinPred		1.0	D
GERP RS		4.6
Varity_R		0.67
gMVP		0.66
Mutation Taster		=15/85	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs80338834; hg19: chr22-36680520;