NM_002473.6:c.*596G>A

Variant names:

• chr22-36282072-C-T
• rs136200
• NM_002473.6:c.*596G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002473.6(MYH9):​c.*596G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.343 in 236,098 control chromosomes in the GnomAD database, including 16,772 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.33 (10100 hom., cov: 33)
  • Exomes 𝑓: 0.37 (6672 hom.)
• Consequence: MYH9 NM_002473.6 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.502
• Publications: 6 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.447 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH9	NM_002473.6	c.*596G>A		3_prime_UTR_variant	Exon 41 of 41	ENST00000216181.11	NP_002464.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYH9	ENST00000216181.11	c.*596G>A		3_prime_UTR_variant	Exon 41 of 41	1	NM_002473.6	ENSP00000216181.6

Frequencies

GnomAD3 genomes AF: 0.326 AC: 49539 AN: 152012 Hom.: 10100 Cov.: 33

Gnomad AFR AF: 0.0897

Gnomad AMI AF: 0.625

Gnomad AMR AF: 0.423

Gnomad ASJ AF: 0.375

Gnomad EAS AF: 0.126

Gnomad SAS AF: 0.219

Gnomad FIN AF: 0.403

Gnomad MID AF: 0.323

Gnomad NFE AF: 0.452

Gnomad OTH AF: 0.351

GnomAD4 exome AF: 0.374 AC: 31392 AN: 83968 Hom.: 6672 Cov.: 0 AF XY: 0.376 AC XY: 14634 AN XY: 38914

African (AFR) AF: 0.0814 AC: 312 AN: 3834

American (AMR) AF: 0.414 AC: 1460 AN: 3524

Ashkenazi Jewish (ASJ) AF: 0.373 AC: 1878 AN: 5036

East Asian (EAS) AF: 0.129 AC: 1468 AN: 11396

South Asian (SAS) AF: 0.214 AC: 233 AN: 1090

European-Finnish (FIN) AF: 0.419 AC: 207 AN: 494

Middle Eastern (MID) AF: 0.378 AC: 185 AN: 490

European-Non Finnish (NFE) AF: 0.450 AC: 23107 AN: 51304

Other (OTH) AF: 0.374 AC: 2542 AN: 6800

GnomAD4 genome AF: 0.326 AC: 49534 AN: 152130 Hom.: 10100 Cov.: 33 AF XY: 0.323 AC XY: 24005 AN XY: 74368

African (AFR) AF: 0.0894 AC: 3716 AN: 41546

American (AMR) AF: 0.423 AC: 6467 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.375 AC: 1300 AN: 3470

East Asian (EAS) AF: 0.126 AC: 651 AN: 5160

South Asian (SAS) AF: 0.220 AC: 1057 AN: 4814

European-Finnish (FIN) AF: 0.403 AC: 4263 AN: 10588

Middle Eastern (MID) AF: 0.316 AC: 93 AN: 294

European-Non Finnish (NFE) AF: 0.452 AC: 30686 AN: 67944

Other (OTH) AF: 0.348 AC: 735 AN: 2114

Alfa AF: 0.381 Hom.: 3359

Bravo AF: 0.319

Asia WGS AF: 0.151 AC: 525 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

May 13, 2021

GeneDx

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

- -

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. -

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	-0.89
CADD	Benign	0.44
DANN	Benign	0.39
PhyloP100		-0.50
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: rs136200; hg19: chr22-36678118; COSMIC: COSV53387701; COSMIC: COSV53387701;