22-36288285-C-T

Variant names:

• chr22-36288285-C-T
• rs5756130
• NM_002473.6:c.4899G>A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_002473.6(MYH9):​c.4899G>A​(p.Arg1633Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0538 in 1,614,018 control chromosomes in the GnomAD database, including 2,962 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.072 (469 hom., cov: 33)
  • Exomes 𝑓: 0.052 (2493 hom.)
• Consequence: MYH9 NM_002473.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.725

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 22-36288285-C-T is Benign according to our data. Variant chr22-36288285-C-T is described in ClinVar as [Benign]. Clinvar id is 44566.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-36288285-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.725 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.117 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH9	NM_002473.6	c.4899G>A	p.Arg1633Arg	synonymous_variant	Exon 34 of 41	ENST00000216181.11	NP_002464.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYH9	ENST00000216181.11	c.4899G>A	p.Arg1633Arg	synonymous_variant	Exon 34 of 41	1	NM_002473.6	ENSP00000216181.6
MYH9	ENST00000685801.1	c.4962G>A	p.Arg1654Arg	synonymous_variant	Exon 35 of 42			ENSP00000510688.1
MYH9	ENST00000691109.1	n.5194G>A		non_coding_transcript_exon_variant	Exon 28 of 35
MYH9	ENST00000685708.1	n.-74G>A		upstream_gene_variant

Frequencies

GnomAD3 genomes AF: 0.0724 AC: 11013 AN: 152102 Hom.: 468 Cov.: 33

Gnomad AFR AF: 0.120

Gnomad AMI AF: 0.0176

Gnomad AMR AF: 0.0866

Gnomad ASJ AF: 0.0380

Gnomad EAS AF: 0.0914

Gnomad SAS AF: 0.0728

Gnomad FIN AF: 0.0598

Gnomad MID AF: 0.0791

Gnomad NFE AF: 0.0434

Gnomad OTH AF: 0.0665

GnomAD3 exomes AF: 0.0714 AC: 17958 AN: 251380 Hom.: 834 AF XY: 0.0680 AC XY: 9236 AN XY: 135870

Gnomad AFR exome AF: 0.118

Gnomad AMR exome AF: 0.133

Gnomad ASJ exome AF: 0.0475

Gnomad EAS exome AF: 0.0986

Gnomad SAS exome AF: 0.0786

Gnomad FIN exome AF: 0.0652

Gnomad NFE exome AF: 0.0435

Gnomad OTH exome AF: 0.0627

GnomAD4 exome AF: 0.0519 AC: 75800 AN: 1461798 Hom.: 2493 Cov.: 33 AF XY: 0.0523 AC XY: 38017 AN XY: 727204

Gnomad4 AFR exome AF: 0.125

Gnomad4 AMR exome AF: 0.127

Gnomad4 ASJ exome AF: 0.0445

Gnomad4 EAS exome AF: 0.0940

Gnomad4 SAS exome AF: 0.0760

Gnomad4 FIN exome AF: 0.0675

Gnomad4 NFE exome AF: 0.0426

Gnomad4 OTH exome AF: 0.0536

GnomAD4 genome AF: 0.0724 AC: 11017 AN: 152220 Hom.: 469 Cov.: 33 AF XY: 0.0720 AC XY: 5359 AN XY: 74436

Gnomad4 AFR AF: 0.120

Gnomad4 AMR AF: 0.0863

Gnomad4 ASJ AF: 0.0380

Gnomad4 EAS AF: 0.0910

Gnomad4 SAS AF: 0.0718

Gnomad4 FIN AF: 0.0598

Gnomad4 NFE AF: 0.0434

Gnomad4 OTH AF: 0.0658

Alfa AF: 0.0513 Hom.: 321

Bravo AF: 0.0774

Asia WGS AF: 0.0690 AC: 238 AN: 3478

EpiCase AF: 0.0416

EpiControl AF: 0.0402

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 07, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Arg1633Arg 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 11.1% (414/3738) of African American chromosomes from a broad population by the NHLBI Exome Sequenci ng Project (http://evs.gs.washington.edu/EVS; dbSNP rs5756130). -

May 09, 2017

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not provided Benign:3

Oct 27, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal dominant nonsyndromic hearing loss 17 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

MYH9-related disorder Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	-0.76
CADD	Benign	4.7
DANN	Benign	0.53
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

Other links and lift over

dbSNP: rs5756130; hg19: chr22-36684331; COSMIC: COSV53392170; COSMIC: COSV53392170;