rs875725

Variant names:

• chr22-36295645-T-C
• rs875725
• NM_002473.6:c.3345A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_002473.6(MYH9):​c.3345A>G​(p.Glu1115Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0159 in 1,613,868 control chromosomes in the GnomAD database, including 404 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.031 (120 hom., cov: 32)
  • Exomes 𝑓: 0.014 (284 hom.)
• Consequence: MYH9 NM_002473.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.392
• Publications: 10 publications found

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 Gene-Disease associations (from GenCC):

• autosomal dominant nonsyndromic hearing loss 17

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• macrothrombocytopenia and granulocyte inclusions with or without nephritis or sensorineural hearing loss

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae), ClinGen
• May-Hegglin anomaly

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• autosomal dominant nonsyndromic hearing loss

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.64).
• BP6: Variant 22-36295645-T-C is Benign according to our data. Variant chr22-36295645-T-C is described in ClinVar as [Benign]. Clinvar id is 44558.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.392 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0719 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH9	NM_002473.6	c.3345A>G	p.Glu1115Glu	synonymous_variant	Exon 26 of 41	ENST00000216181.11	NP_002464.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYH9	ENST00000216181.11	c.3345A>G	p.Glu1115Glu	synonymous_variant	Exon 26 of 41	1	NM_002473.6	ENSP00000216181.6
MYH9	ENST00000685801.1	c.3408A>G	p.Glu1136Glu	synonymous_variant	Exon 27 of 42			ENSP00000510688.1
MYH9	ENST00000459960.1	n.554A>G		non_coding_transcript_exon_variant	Exon 2 of 2	2
MYH9	ENST00000691109.1	n.3640A>G		non_coding_transcript_exon_variant	Exon 20 of 35

Frequencies

GnomAD3 genomes AF: 0.0310 AC: 4717 AN: 152112 Hom.: 120 Cov.: 32

Gnomad AFR AF: 0.0742

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.0250

Gnomad ASJ AF: 0.0208

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00829

Gnomad FIN AF: 0.0185

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.0127

Gnomad OTH AF: 0.0296

GnomAD2 exomes AF: 0.0168 AC: 4205 AN: 250798 AF XY: 0.0153

Gnomad AFR exome AF: 0.0742

Gnomad AMR exome AF: 0.0154

Gnomad ASJ exome AF: 0.0200

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.0183

Gnomad NFE exome AF: 0.0129

Gnomad OTH exome AF: 0.0235

GnomAD4 exome AF: 0.0144 AC: 21011 AN: 1461638 Hom.: 284 Cov.: 35 AF XY: 0.0140 AC XY: 10190 AN XY: 727106

African (AFR) AF: 0.0781 AC: 2614 AN: 33478

American (AMR) AF: 0.0156 AC: 696 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.0193 AC: 503 AN: 26128

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00936 AC: 807 AN: 86228

European-Finnish (FIN) AF: 0.0187 AC: 996 AN: 53252

Middle Eastern (MID) AF: 0.0780 AC: 450 AN: 5766

European-Non Finnish (NFE) AF: 0.0124 AC: 13790 AN: 1111978

Other (OTH) AF: 0.0191 AC: 1154 AN: 60390

GnomAD4 genome AF: 0.0310 AC: 4722 AN: 152230 Hom.: 120 Cov.: 32 AF XY: 0.0305 AC XY: 2270 AN XY: 74428

African (AFR) AF: 0.0741 AC: 3078 AN: 41520

American (AMR) AF: 0.0250 AC: 383 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0208 AC: 72 AN: 3466

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5172

South Asian (SAS) AF: 0.00808 AC: 39 AN: 4824

European-Finnish (FIN) AF: 0.0185 AC: 196 AN: 10616

Middle Eastern (MID) AF: 0.0748 AC: 22 AN: 294

European-Non Finnish (NFE) AF: 0.0127 AC: 865 AN: 68022

Other (OTH) AF: 0.0293 AC: 62 AN: 2114

Alfa AF: 0.0238 Hom.: 144

Bravo AF: 0.0329

Asia WGS AF: 0.0120 AC: 43 AN: 3478

EpiCase AF: 0.0154

EpiControl AF: 0.0153

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Feb 15, 2019

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 29, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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

- -

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

Glu1115Glu 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 7.7% (287/3734) of A frican American chromosomes from a broad population by the NHLBI Exome Sequencin g Project (http://evs.gs.washington.edu/EVS; dbSNP rs875725). -

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. -

Autosomal dominant nonsyndromic hearing loss 17 Benign:1

Jan 12, 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. -

Atypical hemolytic-uremic syndrome Benign:1

Aug 06, 2022

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

MYH9-related disorder Benign:1

Jan 12, 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	-0.64
CADD	Benign	7.4
DANN	Benign	0.63
PhyloP100		0.39
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs875725; hg19: chr22-36691691;