rs138436678

chr22-36316655-G-Achr22-36316655-G-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_002473.6(MYH9):c.1242C>T(p.Ile414=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0011 in 1,613,938 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00082 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (2 hom.)
• Consequence: MYH9 NM_002473.6 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.0780

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=-0.59).
• BP6: Variant 22-36316655-G-A is Benign according to our data. Variant chr22-36316655-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 178436.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-36316655-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.078 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000821 (125/152320) while in subpopulation AMR AF= 0.00144 (22/15304). AF 95% confidence interval is 0.000972. There are 0 homozygotes in gnomad4. There are 62 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 126 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH9	NM_002473.6	c.1242C>T	p.Ile414=	synonymous_variant	12/41	ENST00000216181.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH9	ENST00000216181.11	c.1242C>T	p.Ile414=	synonymous_variant	12/41	1	NM_002473.6	P1

Frequencies

GnomAD3 genomes AF: 0.000828 AC: 126 AN: 152202 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000555

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00144

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000941

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00109 AC: 272 AN: 250402 Hom.: 2 AF XY: 0.00128 AC XY: 173 AN XY: 135458

Gnomad AFR exome AF: 0.000556

Gnomad AMR exome AF: 0.000695

Gnomad ASJ exome AF: 0.00309

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00245

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.00111

Gnomad OTH exome AF: 0.00115

GnomAD4 exome AF: 0.00113 AC: 1647 AN: 1461618 Hom.: 2 Cov.: 34 AF XY: 0.00122 AC XY: 888 AN XY: 727082

Gnomad4 AFR exome AF: 0.000568

Gnomad4 AMR exome AF: 0.000559

Gnomad4 ASJ exome AF: 0.00287

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00216

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00112

Gnomad4 OTH exome AF: 0.00126

GnomAD4 genome AF: 0.000821 AC: 125 AN: 152320 Hom.: 0 Cov.: 32 AF XY: 0.000832 AC XY: 62 AN XY: 74488

Gnomad4 AFR AF: 0.000553

Gnomad4 AMR AF: 0.00144

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.000941

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00117 Hom.: 2

Bravo AF: 0.00105

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.00169

EpiControl AF: 0.00154

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2023	MYH9: BP4, BP7, BS1 -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 18, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 15, 2020	- -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 30, 2012	p.Ile414Ile in exon 12 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 0.1% (9/8600) of Eur opean American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs. washington.edu/EVS; dbSNP rs138436678). -

Autosomal dominant nonsyndromic hearing loss 17 Benign:1

Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

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	-0.59
Cadd	Benign	2.5
Dann	Benign	0.90

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: rs138436678; hg19: chr22-36712700; COSMIC: COSV53393958; COSMIC: COSV53393958;