rs875725

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_002473.6(MYH9):c.3345A>G(p.Glu1115=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0159 in 1,613,868 control chromosomes in the GnomAD database, including 404 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.031 ( 120 hom., cov: 32)

Exomes 𝑓: 0.014 ( 284 hom. )

Consequence

MYH9
NM_002473.6 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 0.392

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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.64).

BP6

Variant 22-36295645-T-C is Benign according to our data. Variant chr22-36295645-T-C is described in ClinVar as [Benign]. Clinvar id is 44558.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-36295645-T-C is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=0.392 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0719 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH9	NM_002473.6 linkuse as main transcript	c.3345A>G	p.Glu1115=	synonymous_variant	26/41	ENST00000216181.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH9	ENST00000216181.11 linkuse as main transcript	c.3345A>G	p.Glu1115=	synonymous_variant	26/41	1	NM_002473.6	P1	P35579-1
MYH9	ENST00000685801.1 linkuse as main transcript	c.3408A>G	p.Glu1136=	synonymous_variant	27/42
MYH9	ENST00000459960.1 linkuse as main transcript	n.554A>G		non_coding_transcript_exon_variant	2/2	2
MYH9	ENST00000691109.1 linkuse as main transcript	n.3640A>G		non_coding_transcript_exon_variant	20/35

Frequencies

GnomAD3 genomes

AF:

0.0310

AC:

4717

AN:

152112

Hom.:

120

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0742

Gnomad AMI

AF:

0.00439

Gnomad AMR

AF:

0.0250

Gnomad ASJ

AF:

0.0208

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00829

Gnomad FIN

AF:

0.0185

Gnomad MID

AF:

0.0696

Gnomad NFE

AF:

0.0127

Gnomad OTH

AF:

0.0296

GnomAD3 exomes

AF:

0.0168

AC:

4205

AN:

250798

Hom.:

AF XY:

0.0153

AC XY:

2081

AN XY:

135670

show subpopulations

Gnomad AFR exome

AF:

0.0742

Gnomad AMR exome

AF:

0.0154

Gnomad ASJ exome

AF:

0.0200

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00873

Gnomad FIN exome

AF:

0.0183

Gnomad NFE exome

AF:

0.0129

Gnomad OTH exome

AF:

0.0235

GnomAD4 exome

AF:

0.0144

AC:

21011

AN:

1461638

Hom.:

284

Cov.:

AF XY:

0.0140

AC XY:

10190

AN XY:

727106

show subpopulations

Gnomad4 AFR exome

AF:

0.0781

Gnomad4 AMR exome

AF:

0.0156

Gnomad4 ASJ exome

AF:

0.0193

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00936

Gnomad4 FIN exome

AF:

0.0187

Gnomad4 NFE exome

AF:

0.0124

Gnomad4 OTH exome

AF:

0.0191

GnomAD4 genome

AF:

0.0310

AC:

4722

AN:

152230

Hom.:

120

Cov.:

AF XY:

0.0305

AC XY:

2270

AN XY:

74428

show subpopulations

Gnomad4 AFR

AF:

0.0741

Gnomad4 AMR

AF:

0.0250

Gnomad4 ASJ

AF:

0.0208

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00808

Gnomad4 FIN

AF:

0.0185

Gnomad4 NFE

AF:

0.0127

Gnomad4 OTH

AF:

0.0293

Alfa

AF:

0.0190

Hom.:

Bravo

AF:

0.0329

Asia WGS

AF:

0.0120

AC:

AN:

3478

EpiCase

AF:

0.0154

EpiControl

AF:

0.0153

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 09, 2017	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. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 07, 2012	Glu1115Glu in Exon 26 of MYH9: This variant is not expected to have clinical si gnificance because it does not alter an amino acid residue, is not located withi n the splice consensus sequence, and has been identified in 7.7% (287/3734) of A frican American chromosomes from a broad population by the NHLBI Exome Sequencin g Project (http://evs.gs.washington.edu/EVS; dbSNP rs875725). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Feb 15, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -

Autosomal dominant nonsyndromic hearing loss 17

Benign:1

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. -

Atypical hemolytic-uremic syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Aug 06, 2022

- -

MYH9-related disorder

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.64

Cadd

Benign

7.4

Dann

Benign

0.63

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