rs2269529

Variant names:

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBA1

The NM_002473.6(MYH9):c.4876A>G(p.Ile1626Val) variant causes a missense change. The variant allele was found at a frequency of 0.219 in 1,613,510 control chromosomes in the GnomAD database, including 47,050 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. I1626I) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.19 ( 3716 hom., cov: 32)

Exomes 𝑓: 0.22 ( 43334 hom. )

Consequence

MYH9
NM_002473.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:15

Conservation

PhyloP100: 4.02

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

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.

BP4

Computational evidence support a benign effect (MetaRNN=3.1029584E-5).

BP6

Variant 22-36288308-T-C is Benign according to our data. Variant chr22-36288308-T-C is described in ClinVar as [Benign]. Clinvar id is 38967.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-36288308-T-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.588 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH9	NM_002473.6 link	c.4876A>G	p.Ile1626Val	missense_variant	Exon 34 of 41	ENST00000216181.11	NP_002464.1	P35579-1A0A024R1N1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
MYH9	ENST00000216181.11 link	c.4876A>G	p.Ile1626Val	missense_variant	Exon 34 of 41	1	NM_002473.6	ENSP00000216181.6	P35579-1
MYH9	ENST00000685801.1 link	c.4939A>G	p.Ile1647Val	missense_variant	Exon 35 of 42			ENSP00000510688.1	A0A8I5KWT8
MYH9	ENST00000691109.1 link	n.5171A>G		non_coding_transcript_exon_variant	Exon 28 of 35
MYH9	ENST00000685708.1 link	n.-97A>G		upstream_gene_variant

Frequencies

GnomAD3 genomes

AF:

0.190

AC:

28802

AN:

151840

Hom.:

3702

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0718

Gnomad AMI

AF:

0.177

Gnomad AMR

AF:

0.248

Gnomad ASJ

AF:

0.346

Gnomad EAS

AF:

0.605

Gnomad SAS

AF:

0.455

Gnomad FIN

AF:

0.179

Gnomad MID

AF:

0.266

Gnomad NFE

AF:

0.191

Gnomad OTH

AF:

0.222

GnomAD3 exomes

AF:

0.265

AC:

66555

AN:

251290

Hom.:

11216

AF XY:

0.274

AC XY:

37150

AN XY:

135830

show subpopulations

Gnomad AFR exome

AF:

0.0697

Gnomad AMR exome

AF:

0.286

Gnomad ASJ exome

AF:

0.351

Gnomad EAS exome

AF:

0.611

Gnomad SAS exome

AF:

0.437

Gnomad FIN exome

AF:

0.177

Gnomad NFE exome

AF:

0.194

Gnomad OTH exome

AF:

0.247

GnomAD4 exome

AF:

0.222

AC:

324972

AN:

1461550

Hom.:

43334

Cov.:

AF XY:

0.229

AC XY:

166794

AN XY:

727090

show subpopulations

Gnomad4 AFR exome

AF:

0.0674

Gnomad4 AMR exome

AF:

0.281

Gnomad4 ASJ exome

AF:

0.351

Gnomad4 EAS exome

AF:

0.609

Gnomad4 SAS exome

AF:

0.433

Gnomad4 FIN exome

AF:

0.174

Gnomad4 NFE exome

AF:

0.192

Gnomad4 OTH exome

AF:

0.248

GnomAD4 genome

AF:

0.190

AC:

28843

AN:

151960

Hom.:

3716

Cov.:

AF XY:

0.198

AC XY:

14710

AN XY:

74250

show subpopulations

Gnomad4 AFR

AF:

0.0719

Gnomad4 AMR

AF:

0.249

Gnomad4 ASJ

AF:

0.346

Gnomad4 EAS

AF:

0.606

Gnomad4 SAS

AF:

0.454

Gnomad4 FIN

AF:

0.179

Gnomad4 NFE

AF:

0.191

Gnomad4 OTH

AF:

0.228

Alfa

AF:

0.210

Hom.:

7204

Bravo

AF:

0.190

TwinsUK

AF:

0.190

AC:

706

ALSPAC

AF:

0.193

AC:

744

ESP6500AA

AF:

0.0724

AC:

319

ESP6500EA

AF:

0.198

AC:

1704

ExAC

AF:

0.258

AC:

31375

Asia WGS

AF:

0.525

AC:

1826

AN:

3478

EpiCase

AF:

0.209

EpiControl

AF:

0.209

ClinVar

Significance: Benign

Submissions summary: Benign:15

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:7

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 09, 2017

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Jul 15, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 38% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 35. Only high quality variants are reported. -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 07, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 12, 2015

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 22, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Autosomal dominant nonsyndromic hearing loss 17

Benign:2

Sep 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

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

Benign:1

Sep 25, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Macrothrombocytopenia and granulocyte inclusions with or without nephritis or sensorineural hearing loss

Benign:1

Sep 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

MYH9-related disorder

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.087

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.48

CADD

Benign

DANN

Benign

0.72

DEOGEN2

Benign

0.27

Eigen

Benign

-0.28

Eigen_PC

Benign

-0.14

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.80

MetaRNN

Benign

0.000031

MetaSVM

Benign

-0.91

MutationAssessor

Benign

0.81

PrimateAI

Benign

0.44

PROVEAN

Benign

-0.37

REVEL

Benign

0.22

Sift

Benign

0.33

Sift4G

Benign

0.16

Polyphen

0.042

Vest4

0.057

MPC

0.42

ClinPred

0.0072

GERP RS

4.5

RBP_binding_hub_radar

1.0

RBP_regulation_power_radar

2.7

Varity_R

0.076

gMVP

0.11

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over