22-36285117-G-C

Position:

chr22-36285117-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_002473.6(MYH9):c.5483+4C>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.02 in 1,613,594 control chromosomes in the GnomAD database, including 387 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.015 ( 26 hom., cov: 33)

Exomes 𝑓: 0.021 ( 361 hom. )

Consequence

MYH9
NM_002473.6 splice_region, intron

Scores

Splicing: ADA: 0.0002236

Clinical Significance

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

Conservation

PhyloP100: -1.31

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.71).

BP6

Variant 22-36285117-G-C is Benign according to our data. Variant chr22-36285117-G-C is described in ClinVar as [Benign]. Clinvar id is 44570.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-36285117-G-C is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0152 (2309/152352) while in subpopulation NFE AF= 0.0224 (1524/68026). AF 95% confidence interval is 0.0215. There are 26 homozygotes in gnomad4. There are 1095 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 2309 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYH9	NM_002473.6 linkuse as main transcript	c.5483+4C>G		splice_region_variant, intron_variant		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.5483+4C>G		splice_region_variant, intron_variant		1	NM_002473.6	ENSP00000216181.6		P35579-1

Frequencies

GnomAD3 genomes

AF:

0.0152

AC:

2310

AN:

152234

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00412

Gnomad AMI

AF:

0.00658

Gnomad AMR

AF:

0.00988

Gnomad ASJ

AF:

0.0118

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00186

Gnomad FIN

AF:

0.0355

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.0224

Gnomad OTH

AF:

0.0124

GnomAD3 exomes

AF:

0.0158

AC:

3933

AN:

249710

Hom.:

AF XY:

0.0158

AC XY:

2133

AN XY:

135078

show subpopulations

Gnomad AFR exome

AF:

0.00308

Gnomad AMR exome

AF:

0.00478

Gnomad ASJ exome

AF:

0.0158

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00310

Gnomad FIN exome

AF:

0.0312

Gnomad NFE exome

AF:

0.0239

Gnomad OTH exome

AF:

0.0170

GnomAD4 exome

AF:

0.0205

AC:

30014

AN:

1461242

Hom.:

361

Cov.:

AF XY:

0.0200

AC XY:

14564

AN XY:

726922

show subpopulations

Gnomad4 AFR exome

AF:

0.00260

Gnomad4 AMR exome

AF:

0.00510

Gnomad4 ASJ exome

AF:

0.0143

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00353

Gnomad4 FIN exome

AF:

0.0331

Gnomad4 NFE exome

AF:

0.0235

Gnomad4 OTH exome

AF:

0.0188

GnomAD4 genome

AF:

0.0152

AC:

2309

AN:

152352

Hom.:

Cov.:

AF XY:

0.0147

AC XY:

1095

AN XY:

74496

show subpopulations

Gnomad4 AFR

AF:

0.00414

Gnomad4 AMR

AF:

0.00986

Gnomad4 ASJ

AF:

0.0118

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00207

Gnomad4 FIN

AF:

0.0355

Gnomad4 NFE

AF:

0.0224

Gnomad4 OTH

AF:

0.0123

Alfa

AF:

0.00957

Hom.:

Bravo

AF:

0.0139

Asia WGS

AF:

0.00289

AC:

AN:

3478

EpiCase

AF:

0.0190

EpiControl

AF:

0.0191

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 06, 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	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 07, 2012	5483+4C>G in Intron 38 of MYH9: This variant is not expected to have clinical si gnificance because it has been identified in 2.3% (163/7020) of European America n chromosomes from a broad population by the NHLBI Exome Sequencing Project (htt p://evs.gs.washington.edu/EVS; dbSNP rs56327920). -

not provided

Benign:4

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 27, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 20, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Autosomal dominant nonsyndromic hearing loss 17

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. -

Kidney disorder

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Nov 16, 2021

- -

MYH9-related disorder

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.71

CADD

Benign

0.26

DANN

Benign

0.76

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00022

dbscSNV1_RF

Benign

0.042

SpliceAI score (max)

0.040

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