rs11549907

Variant names:

• chr22-36288934-G-A
• rs11549907
• NM_002473.6:c.4563C>T

Your query was ambiguous. Multiple possible variants found:

• chr22-36288934-G-A
• chr22-36288934-G-T

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.4563C>T​(p.His1521His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0186 in 1,613,760 control chromosomes in the GnomAD database, including 727 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.036 (178 hom., cov: 32)
  • Exomes 𝑓: 0.017 (549 hom.)
• Consequence: MYH9 NM_002473.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -0.560

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=-0.78).
• BP6: Variant 22-36288934-G-A is Benign according to our data. Variant chr22-36288934-G-A is described in ClinVar as [Benign]. Clinvar id is 44563.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-36288934-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.56 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.1 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH9	NM_002473.6	c.4563C>T	p.His1521His	synonymous_variant	Exon 33 of 41	ENST00000216181.11	NP_002464.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYH9	ENST00000216181.11	c.4563C>T	p.His1521His	synonymous_variant	Exon 33 of 41	1	NM_002473.6	ENSP00000216181.6
MYH9	ENST00000685801.1	c.4626C>T	p.His1542His	synonymous_variant	Exon 34 of 42			ENSP00000510688.1
MYH9	ENST00000691109.1	n.4858C>T		non_coding_transcript_exon_variant	Exon 27 of 35

Frequencies

GnomAD3 genomes AF: 0.0356 AC: 5409 AN: 152090 Hom.: 178 Cov.: 32

Gnomad AFR AF: 0.0614

Gnomad AMI AF: 0.00440

Gnomad AMR AF: 0.105

Gnomad ASJ AF: 0.0211

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00830

Gnomad FIN AF: 0.0184

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.0127

Gnomad OTH AF: 0.0321

GnomAD3 exomes AF: 0.0284 AC: 7134 AN: 251068 Hom.: 276 AF XY: 0.0243 AC XY: 3293 AN XY: 135734

Gnomad AFR exome AF: 0.0605

Gnomad AMR exome AF: 0.105

Gnomad ASJ exome AF: 0.0201

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00879

Gnomad FIN exome AF: 0.0185

Gnomad NFE exome AF: 0.0129

Gnomad OTH exome AF: 0.0328

GnomAD4 exome AF: 0.0169 AC: 24677 AN: 1461552 Hom.: 549 Cov.: 34 AF XY: 0.0161 AC XY: 11738 AN XY: 727100

Gnomad4 AFR exome AF: 0.0647

Gnomad4 AMR exome AF: 0.105

Gnomad4 ASJ exome AF: 0.0193

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.00947

Gnomad4 FIN exome AF: 0.0187

Gnomad4 NFE exome AF: 0.0124

Gnomad4 OTH exome AF: 0.0212

GnomAD4 genome AF: 0.0355 AC: 5409 AN: 152208 Hom.: 178 Cov.: 32 AF XY: 0.0366 AC XY: 2722 AN XY: 74414

Gnomad4 AFR AF: 0.0613

Gnomad4 AMR AF: 0.104

Gnomad4 ASJ AF: 0.0211

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00810

Gnomad4 FIN AF: 0.0184

Gnomad4 NFE AF: 0.0127

Gnomad4 OTH AF: 0.0317

Alfa AF: 0.0162 Hom.: 24

Bravo AF: 0.0414

Asia WGS AF: 0.0140 AC: 52 AN: 3478

EpiCase AF: 0.0154

EpiControl AF: 0.0151

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Jul 15, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 26% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 24. Only high quality variants are reported. -

May 07, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

His1521His in Exon 33 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 5.8% (217/3738) of A frican American chromosomes from a broad population by the NHLBI Exome Sequencin g Project (http://evs.gs.washington.edu/EVS; dbSNP rs11549907). -

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. -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:4

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 15, 2024

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

- -

Nov 12, 2018

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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	-0.78
CADD	Benign	0.94
DANN	Benign	0.49
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.7

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: rs11549907; hg19: chr22-36684980; COSMIC: COSV53384859; COSMIC: COSV53384859;