rs710181

Positions:

Variant summary

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

The NM_002473.6(MYH9):c.3429T>G(p.Ala1143Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.976 in 1,613,802 control chromosomes in the GnomAD database, including 768,040 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.97 ( 72088 hom., cov: 30)

Exomes 𝑓: 0.98 ( 695952 hom. )

Consequence

MYH9
NM_002473.6 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: -3.27

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=-0.91).

BP6

Variant 22-36295561-A-C is Benign according to our data. Variant chr22-36295561-A-C is described in ClinVar as [Benign]. Clinvar id is 44559.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-36295561-A-C is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-3.27 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.976 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYH9	NM_002473.6 link	c.3429T>G	p.Ala1143Ala	synonymous_variant	26/41	ENST00000216181.11	NP_002464.1	P35579-1A0A024R1N1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
MYH9	ENST00000216181.11 link	c.3429T>G	p.Ala1143Ala	synonymous_variant	26/41	1	NM_002473.6	ENSP00000216181.6	P35579-1
MYH9	ENST00000685801.1 link	c.3492T>G	p.Ala1164Ala	synonymous_variant	27/42			ENSP00000510688.1	A0A8I5KWT8
MYH9	ENST00000459960.1 link	n.638T>G		non_coding_transcript_exon_variant	2/2	2
MYH9	ENST00000691109.1 link	n.3724T>G		non_coding_transcript_exon_variant	20/35

Frequencies

GnomAD3 genomes

AF:

0.973

AC:

148006

AN:

152072

Hom.:

72020

Cov.:

show subpopulations

Gnomad AFR

AF:

0.971

Gnomad AMI

AF:

0.995

Gnomad AMR

AF:

0.981

Gnomad ASJ

AF:

0.958

Gnomad EAS

AF:

0.999

Gnomad SAS

AF:

0.984

Gnomad FIN

AF:

0.963

Gnomad MID

AF:

0.940

Gnomad NFE

AF:

0.972

Gnomad OTH

AF:

0.971

GnomAD3 exomes

AF:

0.977

AC:

245234

AN:

251110

Hom.:

119761

AF XY:

0.977

AC XY:

132626

AN XY:

135804

show subpopulations

Gnomad AFR exome

AF:

0.972

Gnomad AMR exome

AF:

0.987

Gnomad ASJ exome

AF:

0.964

Gnomad EAS exome

AF:

1.00

Gnomad SAS exome

AF:

0.986

Gnomad FIN exome

AF:

0.961

Gnomad NFE exome

AF:

0.972

Gnomad OTH exome

AF:

0.976

GnomAD4 exome

AF:

0.976

AC:

1426283

AN:

1461612

Hom.:

695952

Cov.:

AF XY:

0.976

AC XY:

709509

AN XY:

727094

show subpopulations

Gnomad4 AFR exome

AF:

0.973

Gnomad4 AMR exome

AF:

0.986

Gnomad4 ASJ exome

AF:

0.961

Gnomad4 EAS exome

AF:

1.00

Gnomad4 SAS exome

AF:

0.985

Gnomad4 FIN exome

AF:

0.963

Gnomad4 NFE exome

AF:

0.975

Gnomad4 OTH exome

AF:

0.976

GnomAD4 genome

AF:

0.973

AC:

148134

AN:

152190

Hom.:

72088

Cov.:

AF XY:

0.973

AC XY:

72405

AN XY:

74406

show subpopulations

Gnomad4 AFR

AF:

0.971

Gnomad4 AMR

AF:

0.981

Gnomad4 ASJ

AF:

0.958

Gnomad4 EAS

AF:

0.999

Gnomad4 SAS

AF:

0.985

Gnomad4 FIN

AF:

0.963

Gnomad4 NFE

AF:

0.972

Gnomad4 OTH

AF:

0.971

Alfa

AF:

0.972

Hom.:

78555

Bravo

AF:

0.975

Asia WGS

AF:

0.990

AC:

3443

AN:

3478

EpiCase

AF:

0.973

EpiControl

AF:

0.973

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

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	Ala1143Ala 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 2.9% (205/7020) of E uropean American chromosomes from a broad population by the NHLBI Exome Sequenci ng Project (http://evs.gs.washington.edu/EVS; dbSNP rs710181). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
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 100% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 93. Only high quality variants are reported. -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

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

Autosomal dominant nonsyndromic hearing loss 17

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -

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 13, 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

-0.91

CADD

Benign

0.12

DANN

Benign

0.53

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

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