rs56200894

Positions:

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBS1BS2

The ENST00000216181.11(MYH9):c.7C>G(p.Gln3Glu) variant causes a missense change. The variant allele was found at a frequency of 0.00246 in 1,614,070 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0022 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0025 ( 6 hom. )

Consequence

MYH9
ENST00000216181.11 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1B:12

Conservation

PhyloP100: 5.18

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 gene, where missense usually causes diseases (based on misZ statistic), MYH9. . Gene score misZ 3.473 (greater than the threshold 3.09). Trascript score misZ 6.1231 (greater than threshold 3.09). GenCC has associacion of gene with 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=0.011276066).

BP6

Variant 22-36349230-G-C is Benign according to our data. Variant chr22-36349230-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 178439.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-36349230-G-C is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0022 (335/152308) while in subpopulation AMR AF= 0.0051 (78/15300). AF 95% confidence interval is 0.00419. There are 1 homozygotes in gnomad4. There are 154 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 335 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYH9	NM_002473.6 linkuse as main transcript	c.7C>G	p.Gln3Glu	missense_variant	2/41	ENST00000216181.11	NP_002464.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYH9	ENST00000216181.11 linkuse as main transcript	c.7C>G	p.Gln3Glu	missense_variant	2/41	1	NM_002473.6	ENSP00000216181	P1	P35579-1

Frequencies

GnomAD3 genomes

AF:

0.00220

AC:

335

AN:

152190

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000772

Gnomad AMI

AF:

0.00658

Gnomad AMR

AF:

0.00510

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000754

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00303

Gnomad OTH

AF:

0.00239

GnomAD3 exomes

AF:

0.00161

AC:

399

AN:

248576

Hom.:

AF XY:

0.00159

AC XY:

214

AN XY:

134652

show subpopulations

Gnomad AFR exome

AF:

0.000557

Gnomad AMR exome

AF:

0.00249

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000196

Gnomad FIN exome

AF:

0.000510

Gnomad NFE exome

AF:

0.00243

Gnomad OTH exome

AF:

0.00278

GnomAD4 exome

AF:

0.00248

AC:

3629

AN:

1461762

Hom.:

Cov.:

AF XY:

0.00241

AC XY:

1752

AN XY:

727190

show subpopulations

Gnomad4 AFR exome

AF:

0.000388

Gnomad4 AMR exome

AF:

0.00271

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000209

Gnomad4 FIN exome

AF:

0.000506

Gnomad4 NFE exome

AF:

0.00298

Gnomad4 OTH exome

AF:

0.00215

GnomAD4 genome

AF:

0.00220

AC:

335

AN:

152308

Hom.:

Cov.:

AF XY:

0.00207

AC XY:

154

AN XY:

74464

show subpopulations

Gnomad4 AFR

AF:

0.000770

Gnomad4 AMR

AF:

0.00510

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000754

Gnomad4 NFE

AF:

0.00303

Gnomad4 OTH

AF:

0.00237

Alfa

AF:

0.00234

Hom.:

Bravo

AF:

0.00235

TwinsUK

AF:

0.00162

AC:

ALSPAC

AF:

0.00337

AC:

ESP6500AA

AF:

0.00113

AC:

ESP6500EA

AF:

0.00302

AC:

ExAC

AF:

0.00147

AC:

178

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00251

EpiControl

AF:

0.00237

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:7

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	MYH9: BS1, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 08, 2020	This variant is associated with the following publications: (PMID: 29090586, 30349881) -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 08, 2023	- -

MYH9-related disorder

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	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. -
Likely benign, no assertion criteria provided	clinical testing	PreventionGenetics, part of Exact Sciences	Oct 30, 2019	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

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

Uncertain:1

Uncertain significance, no assertion criteria provided

research

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

- -

Autosomal dominant nonsyndromic hearing loss 17

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 30, 2012

Gln3Glu in Exon 02 of MYH9: This variant is not expected to have clinical signif icance because it has been identified in 0.3% (24/7020) of European American chr omosomes from a broad population by the NHLBI Exome Sequencing Project (http://e vs.gs.washington.edu/EVS; dbSNP rs56200894). -

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

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Aug 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.081

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Uncertain

-0.030

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.24

T;T;T

Eigen

Benign

0.060

Eigen_PC

Uncertain

0.24

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.91

D;D;D

M_CAP

Benign

0.014

MetaRNN

Benign

0.011

T;T;T

MetaSVM

Benign

-0.29

MutationAssessor

Benign

1.6

L;.;.

MutationTaster

Benign

0.98

D;D

PrimateAI

Uncertain

0.63

PROVEAN

Benign

-0.67

N;N;N

REVEL

Uncertain

0.38

Sift

Uncertain

0.013

D;D;D

Sift4G

Benign

0.41

T;T;T

Polyphen

0.53

P;B;.

Vest4

0.46

MVP

0.86

MPC

1.0

ClinPred

0.018

GERP RS

5.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.17

gMVP

0.31

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