rs201021615

Positions:

• chr22-36285744-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP2 BP6 BS1 BS2

The NM_002473.6(MYH9):​c.5188C>T​(p.Arg1730Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000072 in 1,611,792 control chromosomes in the GnomAD database, including 1 homozygotes. 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. R1730H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000099 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000069 (1 hom.)
• Consequence: MYH9 NM_002473.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 6.52

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 -8 ACMG points.

• PP2: Missense variant where missense usually causes diseases, MYH9
• BP6: Variant 22-36285744-G-A is Benign according to our data. Variant chr22-36285744-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 164417.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=1}.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.0000985 (15/152214) while in subpopulation EAS AF= 0.00135 (7/5198). AF 95% confidence interval is 0.000632. There are 0 homozygotes in gnomad4. There are 12 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 15 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH9	NM_002473.6	c.5188C>T	p.Arg1730Cys	missense_variant	37/41	ENST00000216181.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH9	ENST00000216181.11	c.5188C>T	p.Arg1730Cys	missense_variant	37/41	1	NM_002473.6	P1

Frequencies

GnomAD3 genomes AF: 0.0000985 AC: 15 AN: 152214 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00135

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000146 AC: 36 AN: 246134 Hom.: 0 AF XY: 0.000158 AC XY: 21 AN XY: 133116

Gnomad AFR exome AF: 0.0000635

Gnomad AMR exome AF: 0.0000880

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00111

Gnomad SAS exome AF: 0.000265

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000360

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000692 AC: 101 AN: 1459578 Hom.: 1 Cov.: 32 AF XY: 0.0000647 AC XY: 47 AN XY: 725994

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000113

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00119

Gnomad4 SAS exome AF: 0.000198

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000243

Gnomad4 OTH exome AF: 0.0000830

GnomAD4 genome AF: 0.0000985 AC: 15 AN: 152214 Hom.: 0 Cov.: 33 AF XY: 0.000161 AC XY: 12 AN XY: 74376

Gnomad4 AFR AF: 0.0000724

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00135

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.0000658 Hom.: 0

Bravo AF: 0.0000793

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000214 AC: 26

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 01, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 30, 2020	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27393652) -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jun 10, 2014

The Arg1730Cys variant in MYH9 has not been previously reported in individuals w ith hearing loss, but it was identified in 0.02% (1/4022) of African American ch romosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EV S/; dbSNP rs201021615). Computational prediction tools and conservation analysis suggest that the Arg1730Cys variant may impact the protein, though this informa tion is not predictive enough to determine pathogenicity. In summary, the clinic al significance of the Arg1730Cys variant is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Uncertain	0.072	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.87	D
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.53	D
MetaRNN	Uncertain	0.72	D
MetaSVM	Uncertain	0.43	D
MutationAssessor	Pathogenic	3.4	M
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-6.5	D
REVEL	Pathogenic	0.85
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.88
MVP		0.91
MPC		1.7
ClinPred		0.49	T
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.68
gMVP		0.48

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: rs201021615; hg19: chr22-36681790; COSMIC: COSV53382618; COSMIC: COSV53382618;