NM_002473.6:c.279C>G

Variant names:

• chr22-36348958-G-C
• rs121913655
• NM_002473.6:c.279C>G

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_002473.6(MYH9):​c.279C>G​(p.Asn93Lys) variant causes a missense change involving the alteration of a non-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. N93D) 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 O:1
• Conservation: PhyloP100: 1.16

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 19 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_002473.6
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr22-36348960-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1703781.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, Uncertain_significance=1}.
• PP2: Missense variant in the MYH9 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 43 curated pathogenic missense variants (we use a threshold of 10). The gene has 84 curated benign missense variants. Gene score misZ: 3.473 (above the threshold of 3.09). Trascript score misZ: 6.1231 (above the threshold of 3.09). GenCC associations: The gene is linked to 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, 0.967
• PP5: Variant 22-36348958-G-C is Pathogenic according to our data. Variant chr22-36348958-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 14075.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-36348958-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH9	NM_002473.6	c.279C>G	p.Asn93Lys	missense_variant	Exon 2 of 41	ENST00000216181.11	NP_002464.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYH9	ENST00000216181.11	c.279C>G	p.Asn93Lys	missense_variant	Exon 2 of 41	1	NM_002473.6	ENSP00000216181.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3 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:2 Other:1

-

ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 01, 2000

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

MYH9-related disorder Pathogenic:1

Dec 12, 2018

NIHR Bioresource Rare Diseases, University of Cambridge

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

PS4, PS3, PM1, PM2, PP4, PP3 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.97	D;D;D
Eigen	Uncertain	0.40
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.85	T;T;T
M_CAP	Pathogenic	0.59	D
MetaRNN	Pathogenic	0.97	D;D;D
MetaSVM	Uncertain	0.70	D
MutationAssessor	Pathogenic	3.9	H;.;.
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-5.2	D;D;D
REVEL	Pathogenic	0.71
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0010	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.98
MutPred		0.89		Loss of catalytic residue at N93 (P = 0.0222);Loss of catalytic residue at N93 (P = 0.0222);Loss of catalytic residue at N93 (P = 0.0222);
MVP		0.96
MPC		2.2
ClinPred		1.0	D
GERP RS		-0.96
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.98
gMVP		0.88

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: rs121913655; hg19: chr22-36745003;