rs9619601

chr22-36304129-A-G

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.2256T>C(p.Asn752=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0528 in 1,613,526 control chromosomes in the GnomAD database, including 2,449 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.048 (177 hom., cov: 33)
  • Exomes 𝑓: 0.053 (2272 hom.)
• Consequence: MYH9 NM_002473.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 3.14

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=-0.64).
• BP6: Variant 22-36304129-A-G is Benign according to our data. Variant chr22-36304129-A-G is described in ClinVar as [Benign]. Clinvar id is 44555.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-36304129-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=3.14 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.089 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH9	NM_002473.6	c.2256T>C	p.Asn752=	synonymous_variant	19/41	ENST00000216181.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH9	ENST00000216181.11	c.2256T>C	p.Asn752=	synonymous_variant	19/41	1	NM_002473.6	P1
MYH9	ENST00000685801.1	c.2319T>C	p.Asn773=	synonymous_variant	20/42
MYH9	ENST00000691109.1	n.2551T>C		non_coding_transcript_exon_variant	13/35

Frequencies

GnomAD3 genomes AF: 0.0479 AC: 7285 AN: 152134 Hom.: 178 Cov.: 33

Gnomad AFR AF: 0.0384

Gnomad AMI AF: 0.0296

Gnomad AMR AF: 0.0221

Gnomad ASJ AF: 0.0536

Gnomad EAS AF: 0.0961

Gnomad SAS AF: 0.0691

Gnomad FIN AF: 0.0626

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0520

Gnomad OTH AF: 0.0468

GnomAD3 exomes AF: 0.0533 AC: 13400 AN: 251216 Hom.: 455 AF XY: 0.0549 AC XY: 7455 AN XY: 135892

Gnomad AFR exome AF: 0.0399

Gnomad AMR exome AF: 0.0197

Gnomad ASJ exome AF: 0.0513

Gnomad EAS exome AF: 0.109

Gnomad SAS exome AF: 0.0633

Gnomad FIN exome AF: 0.0658

Gnomad NFE exome AF: 0.0521

Gnomad OTH exome AF: 0.0451

GnomAD4 exome AF: 0.0533 AC: 77951 AN: 1461274 Hom.: 2272 Cov.: 32 AF XY: 0.0536 AC XY: 38974 AN XY: 726928

Gnomad4 AFR exome AF: 0.0367

Gnomad4 AMR exome AF: 0.0197

Gnomad4 ASJ exome AF: 0.0533

Gnomad4 EAS exome AF: 0.0990

Gnomad4 SAS exome AF: 0.0628

Gnomad4 FIN exome AF: 0.0655

Gnomad4 NFE exome AF: 0.0524

Gnomad4 OTH exome AF: 0.0526

GnomAD4 genome AF: 0.0478 AC: 7282 AN: 152252 Hom.: 177 Cov.: 33 AF XY: 0.0477 AC XY: 3553 AN XY: 74452

Gnomad4 AFR AF: 0.0383

Gnomad4 AMR AF: 0.0221

Gnomad4 ASJ AF: 0.0536

Gnomad4 EAS AF: 0.0960

Gnomad4 SAS AF: 0.0684

Gnomad4 FIN AF: 0.0626

Gnomad4 NFE AF: 0.0520

Gnomad4 OTH AF: 0.0478

Alfa AF: 0.0490 Hom.: 244

Bravo AF: 0.0439

Asia WGS AF: 0.0930 AC: 323 AN: 3478

EpiCase AF: 0.0483

EpiControl AF: 0.0494

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 07, 2012	Asn752Asn in Exon 19 of MYH9: This variant is not expected to have clinical sig nificance because it does not alter an amino acid residue, is not located within the splice consensus sequence, and has been identified in 4.6% (322/7020) of Eu ropean American chromosomes from a broad population by the NHLBI Exome Sequencin g Project (http://evs.gs.washington.edu/EVS; dbSNP rs9619601). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 03, 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. -

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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

MYH9-related disorder 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
Cadd	Benign	7.3
Dann	Benign	0.82

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: rs9619601; hg19: chr22-36700175; COSMIC: COSV53386660; COSMIC: COSV53386660;