rs148109368

Positions:

chr22-36285872-C-T

Variant summary

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

The NM_002473.6(MYH9):c.5143G>A(p.Gly1715Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00236 in 1,613,758 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0019 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0024 ( 11 hom. )

Consequence

MYH9
NM_002473.6 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.980

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:

MYH9 (HGNC:):

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=0.009938329).

BP6

Variant 22-36285872-C-T is Benign according to our data. Variant chr22-36285872-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 178425.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-36285872-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00192 (293/152290) while in subpopulation NFE AF= 0.00312 (212/68020). AF 95% confidence interval is 0.00277. There are 0 homozygotes in gnomad4. There are 120 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 293 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYH9	NM_002473.6 linkuse as main transcript	c.5143G>A	p.Gly1715Ser	missense_variant	36/41	ENST00000216181.11	NP_002464.1	P35579-1A0A024R1N1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYH9	ENST00000216181.11 linkuse as main transcript	c.5143G>A	p.Gly1715Ser	missense_variant	36/41	1	NM_002473.6	ENSP00000216181.6		P35579-1

Frequencies

GnomAD3 genomes

AF:

0.00193

AC:

293

AN:

152172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000942

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.00312

Gnomad OTH

AF:

0.00382

GnomAD3 exomes

AF:

0.00152

AC:

381

AN:

250998

Hom.:

AF XY:

0.00142

AC XY:

193

AN XY:

135744

show subpopulations

Gnomad AFR exome

AF:

0.000246

Gnomad AMR exome

AF:

0.00226

Gnomad ASJ exome

AF:

0.000298

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000795

Gnomad NFE exome

AF:

0.00235

Gnomad OTH exome

AF:

0.00196

GnomAD4 exome

AF:

0.00241

AC:

3521

AN:

1461468

Hom.:

Cov.:

AF XY:

0.00226

AC XY:

1646

AN XY:

727106

show subpopulations

Gnomad4 AFR exome

AF:

0.000329

Gnomad4 AMR exome

AF:

0.00228

Gnomad4 ASJ exome

AF:

0.000191

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.0000580

Gnomad4 FIN exome

AF:

0.000980

Gnomad4 NFE exome

AF:

0.00293

Gnomad4 OTH exome

AF:

0.00137

GnomAD4 genome

AF:

0.00192

AC:

293

AN:

152290

Hom.:

Cov.:

AF XY:

0.00161

AC XY:

120

AN XY:

74458

show subpopulations

Gnomad4 AFR

AF:

0.000481

Gnomad4 AMR

AF:

0.00261

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000942

Gnomad4 NFE

AF:

0.00312

Gnomad4 OTH

AF:

0.00378

Alfa

AF:

0.00208

Hom.:

Bravo

AF:

0.00195

TwinsUK

AF:

0.00297

AC:

ALSPAC

AF:

0.00285

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00291

AC:

ExAC

AF:

0.00147

AC:

178

EpiCase

AF:

0.00311

EpiControl

AF:

0.00249

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:6

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 27, 2021	This variant is associated with the following publications: (PMID: 25903641) -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	MYH9: BS1 -

not specified

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 01, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 16, 2017	p.Gly1715Ser in exon 36 of MYH9: This variant is not expected to have clinical s ignificance because it has been identified in 0.2% (304/126554) European chromos omes by the Genome Aggregation Database, including 3 homozygotes (gnomAD, http:/ /gnomad.broadinstitute.org; dbSNP rs148109368). This frequency is higher than e xpected based on the estimated prevalence of 1-9/1,000,000 of MYH9-related disor der (www.orpha.net, MYH9-related disease, Orpha:182050). -

MYH9-related disorder

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. -
Likely benign, no assertion criteria provided	clinical testing	PreventionGenetics, part of Exact Sciences	Mar 31, 2021	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). -

Autosomal dominant nonsyndromic hearing loss 17

Benign:1

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

Kidney disorder

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Apr 01, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.081

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.39

CADD

Benign

DANN

Benign

0.37

DEOGEN2

Benign

0.29

Eigen

Benign

-0.45

Eigen_PC

Benign

-0.29

FATHMM_MKL

Uncertain

0.82

LIST_S2

Uncertain

0.95

M_CAP

Benign

0.032

MetaRNN

Benign

0.0099

MetaSVM

Benign

-0.69

MutationAssessor

Benign

-2.2

PrimateAI

Uncertain

0.68

PROVEAN

Benign

-1.2

REVEL

Benign

0.25

Sift

Benign

0.42

Sift4G

Benign

0.58

Polyphen

0.016

Vest4

0.35

MVP

0.56

MPC

0.50

ClinPred

0.017

GERP RS

5.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.10

gMVP

0.19

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