22-36285250-C-T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PP3_ModerateBS2

The NM_002473.6(MYH9):​c.5354G>A​(p.Arg1785His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000958 in 1,461,822 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1785L) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000096 ( 0 hom. )

Consequence

MYH9
NM_002473.6 missense

Scores

7
10
2

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.61

Publications

0 publications found
Variant links:
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

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PP3
MetaRNN computational evidence supports a deleterious effect, 0.869
BS2
High AC in GnomAdExome4 at 14 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
MYH9NM_002473.6 linkc.5354G>A p.Arg1785His missense_variant Exon 38 of 41 ENST00000216181.11 NP_002464.1 P35579-1A0A024R1N1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
MYH9ENST00000216181.11 linkc.5354G>A p.Arg1785His missense_variant Exon 38 of 41 1 NM_002473.6 ENSP00000216181.6 P35579-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD2 exomes
AF:
0.0000199
AC:
5
AN:
251416
AF XY:
0.00000736
show subpopulations
Gnomad AFR exome
AF:
0.0000615
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000217
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000958
AC:
14
AN:
1461822
Hom.:
0
Cov.:
32
AF XY:
0.00000825
AC XY:
6
AN XY:
727224
show subpopulations
African (AFR)
AF:
0.0000299
AC:
1
AN:
33480
American (AMR)
AF:
0.00
AC:
0
AN:
44724
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26136
East Asian (EAS)
AF:
0.0000756
AC:
3
AN:
39700
South Asian (SAS)
AF:
0.0000116
AC:
1
AN:
86258
European-Finnish (FIN)
AF:
0.0000187
AC:
1
AN:
53348
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
0.00000629
AC:
7
AN:
1112012
Other (OTH)
AF:
0.0000166
AC:
1
AN:
60396
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.486
Heterozygous variant carriers
0
1
2
3
4
5
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
Cov.:
33
ExAC
AF:
0.0000247
AC:
3

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.27
BayesDel_addAF
Uncertain
0.046
T
BayesDel_noAF
Uncertain
0.12
CADD
Pathogenic
32
DANN
Pathogenic
1.0
DEOGEN2
Uncertain
0.76
D
Eigen
Pathogenic
0.89
Eigen_PC
Pathogenic
0.81
FATHMM_MKL
Uncertain
0.95
D
LIST_S2
Uncertain
0.95
D
M_CAP
Pathogenic
0.40
D
MetaRNN
Pathogenic
0.87
D
MetaSVM
Uncertain
0.77
D
MutationAssessor
Pathogenic
3.5
H
PhyloP100
7.6
PrimateAI
Uncertain
0.68
T
PROVEAN
Uncertain
-4.3
D
REVEL
Pathogenic
0.83
Sift
Uncertain
0.0020
D
Sift4G
Uncertain
0.041
D
Polyphen
1.0
D
Vest4
0.77
MutPred
0.52
Loss of MoRF binding (P = 0.0094);
MVP
0.89
MPC
1.6
ClinPred
0.98
D
GERP RS
5.0
Varity_R
0.66
gMVP
0.27
Mutation Taster
=75/25
polymorphism

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

Other links and lift over

dbSNP: rs774015925; hg19: chr22-36681296; API