chr22-36300900-C-T

Variant names:

• chr22-36300900-C-T
• rs727504740
• NM_002473.6:c.2789G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 3P and 5B. PM5 PP3 BP6 BS2

The NM_002473.6(MYH9):​c.2789G>A​(p.Arg930His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000213 in 1,454,138 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R930G) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000021 (0 hom.)
• Consequence: MYH9 NM_002473.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 7.91
• Publications: 1 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: Likely_benign. The variant received -2 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr22-36300901-G-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1691244.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.798
• BP6: Variant 22-36300900-C-T is Benign according to our data. Variant chr22-36300900-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 179251.
• BS2: High AC in GnomAdExome4 at 31 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002473.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH9	NM_002473.6	MANE Select	c.2789G>A	p.Arg930His	missense	Exon 22 of 41	NP_002464.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH9	ENST00000216181.11	TSL:1 MANE Select	c.2789G>A	p.Arg930His	missense	Exon 22 of 41	ENSP00000216181.6
	MYH9	ENST00000685801.1		c.2852G>A	p.Arg951His	missense	Exon 23 of 42	ENSP00000510688.1
	MYH9	ENST00000691109.1		n.3084G>A		non_coding_transcript_exon	Exon 16 of 35

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000814 AC: 2 AN: 245750 AF XY: 0.00000750

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000328

GnomAD4 exome AF: 0.0000213 AC: 31 AN: 1454138 Hom.: 0 Cov.: 32 AF XY: 0.0000193 AC XY: 14 AN XY: 723662

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.0000671 AC: 3 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.0000437 AC: 2 AN: 45764

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.0000207 AC: 23 AN: 1111966

Other (OTH) AF: 0.0000166 AC: 1 AN: 60354

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

May 21, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Arg930His variant in MYH9 has not been previously reported in individuals with hearing loss or MYH9-related disorder. This variant has been identified in 1/11562 Latino chromosomes by the Exome Aggregation Consortium (ExAC, http://ex ac.broadinstitute.org; dbSNP rs727504740). Computational prediction tools and co nservation analyses do not provide strong support for or against an impact to th e protein. In summary, the clinical significance of the p.Arg930His variant is u ncertain.

Macrothrombocytopenia and granulocyte inclusions with or without nephritis or sensorineural hearing loss Uncertain:1

Dec 07, 2020

Johns Hopkins Genomics, Johns Hopkins University

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has been reported in a patient presenting with hearing loss. MYH9 c.2789G>A (rs727504740) is rare (<0.1%) in a large population dataset (gnomAD: 2/245750 total alleles; 0.0008%; no homozygotes). This variant has been reported in ClinVar. Three bioinformatic tools queried predict that this substitution would be damaging, and the arginine residue at this position is highly evolutionarily conserved across all species assessed. We consider the clinical significance of c.2789G>A to be uncertain at this time.

not provided Benign:1

Oct 18, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.070
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.76	D
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.97	D
M_CAP	Uncertain	0.24	D
MetaRNN	Pathogenic	0.80	D
MetaSVM	Pathogenic	0.90	D
MutationAssessor	Pathogenic	3.1	M
PhyloP100		7.9
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-3.8	D
REVEL	Pathogenic	0.74
Sift	Uncertain	0.018	D
Sift4G	Uncertain	0.046	D
Polyphen		0.99	D
Vest4		0.74
MutPred		0.29		Loss of MoRF binding (P = 0.0755)
MVP		0.89
MPC		1.0
ClinPred		0.99	D
GERP RS		4.2
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.7
Varity_R		0.43
gMVP		0.26
Mutation Taster		=74/26	polymorphism

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: rs727504740; hg19: chr22-36696946;