rs2269530

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The ENST00000216181.11(MYH9):c.4872G>T(p.Ala1624=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.219 in 1,613,466 control chromosomes in the GnomAD database, including 46,971 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A1624A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.19 ( 3705 hom., cov: 32)

Exomes 𝑓: 0.22 ( 43266 hom. )

Consequence

MYH9
ENST00000216181.11 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: -1.15

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.51).

BP6

Variant 22-36288312-C-A is Benign according to our data. Variant chr22-36288312-C-A is described in ClinVar as [Benign]. Clinvar id is 44565.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-36288312-C-A 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/exons	MANE	Protein	UniProt
MYH9	NM_002473.6 linkuse as main transcript	c.4872G>T	p.Ala1624=	synonymous_variant	34/41	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.4872G>T	p.Ala1624=	synonymous_variant	34/41	1	NM_002473.6	ENSP00000216181	P1	P35579-1
MYH9	ENST00000685801.1 linkuse as main transcript	c.4935G>T	p.Ala1645=	synonymous_variant	35/42			ENSP00000510688
MYH9	ENST00000691109.1 linkuse as main transcript	n.5167G>T		non_coding_transcript_exon_variant	28/35

Frequencies

GnomAD3 genomes

AF:

0.189

AC:

28749

AN:

151830

Hom.:

3692

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0709

Gnomad AMI

AF:

0.177

Gnomad AMR

AF:

0.248

Gnomad ASJ

AF:

0.346

Gnomad EAS

AF:

0.605

Gnomad SAS

AF:

0.454

Gnomad FIN

AF:

0.179

Gnomad MID

AF:

0.263

Gnomad NFE

AF:

0.191

Gnomad OTH

AF:

0.221

GnomAD3 exomes

AF:

0.265

AC:

66508

AN:

251282

Hom.:

11198

AF XY:

0.273

AC XY:

37125

AN XY:

135826

show subpopulations

Gnomad AFR exome

AF:

0.0689

Gnomad AMR exome

AF:

0.285

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:

324675

AN:

1461516

Hom.:

43266

Cov.:

AF XY:

0.229

AC XY:

166628

AN XY:

727072

show subpopulations

Gnomad4 AFR exome

AF:

0.0659

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:

0.247

GnomAD4 genome

AF:

0.189

AC:

28789

AN:

151950

Hom.:

3705

Cov.:

AF XY:

0.198

AC XY:

14685

AN XY:

74242

show subpopulations

Gnomad4 AFR

AF:

0.0710

Gnomad4 AMR

AF:

0.249

Gnomad4 ASJ

AF:

0.346

Gnomad4 EAS

AF:

0.606

Gnomad4 SAS

AF:

0.453

Gnomad4 FIN

AF:

0.179

Gnomad4 NFE

AF:

0.191

Gnomad4 OTH

AF:

0.227

Alfa

AF:

0.189

Hom.:

1823

Bravo

AF:

0.189

Asia WGS

AF:

0.525

AC:

1824

AN:

3478

EpiCase

AF:

0.209

EpiControl

AF:

0.209

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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	Ala1624Ala in Exon 34 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 19.8% (1387/7020) of European American chromosomes from a broad population by the NHLBI Exome Sequen cing Project (http://evs.gs.washington.edu/EVS; dbSNP rs2269530). -
Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Jul 15, 2024	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. -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Autosomal dominant nonsyndromic hearing loss 17

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
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. -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 05, 2021

- -

MYH9-related disorder

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.51

CADD

Benign

0.27

DANN

Benign

0.52

RBP_binding_hub_radar

1.0

RBP_regulation_power_radar

2.7

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