rs140588099

Variant names:

• chr22-36282733-C-T
• rs140588099
• NM_002473.6:c.5818G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_002473.6(MYH9):​c.5818G>A​(p.Gly1940Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00262 in 1,613,818 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0015 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0027 (14 hom.)
• Consequence: MYH9 NM_002473.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 2.91
• Publications: 6 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: Labcorp Genetics (formerly Invitae), G2P
• macrothrombocytopenia and granulocyte inclusions with or without nephritis or sensorineural hearing loss

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, ClinGen, Labcorp Genetics (formerly Invitae), Orphanet
• 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.01048705).
• BP6: Variant 22-36282733-C-T is Benign according to our data. Variant chr22-36282733-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 44573.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00146 (222/152342) while in subpopulation NFE AF = 0.00288 (196/68022). AF 95% confidence interval is 0.00255. There are 1 homozygotes in GnomAd4. There are 108 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 222 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH9	NM_002473.6	MANE Select	c.5818G>A	p.Gly1940Arg	missense	Exon 41 of 41	NP_002464.1	P35579-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH9	ENST00000216181.11	TSL:1 MANE Select	c.5818G>A	p.Gly1940Arg	missense	Exon 41 of 41	ENSP00000216181.6	P35579-1
	MYH9	ENST00000685801.1		c.5881G>A	p.Gly1961Arg	missense	Exon 42 of 42	ENSP00000510688.1	A0A8I5KWT8
	MYH9	ENST00000955568.1		c.5881G>A	p.Gly1961Arg	missense	Exon 42 of 42	ENSP00000625627.1

Frequencies

GnomAD3 genomes AF: 0.00146 AC: 223 AN: 152224 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000338

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000659

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00288

Gnomad OTH AF: 0.000957

GnomAD2 exomes AF: 0.00148 AC: 371 AN: 251002 AF XY: 0.00153

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.000260

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000750

Gnomad NFE exome AF: 0.00297

Gnomad OTH exome AF: 0.000652

GnomAD4 exome AF: 0.00274 AC: 4002 AN: 1461476 Hom.: 14 Cov.: 31 AF XY: 0.00268 AC XY: 1949 AN XY: 727044

African (AFR) AF: 0.000418 AC: 14 AN: 33480

American (AMR) AF: 0.000268 AC: 12 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.000115 AC: 3 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.000887 AC: 47 AN: 53016

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00344 AC: 3829 AN: 1112004

Other (OTH) AF: 0.00159 AC: 96 AN: 60392

GnomAD4 genome AF: 0.00146 AC: 222 AN: 152342 Hom.: 1 Cov.: 33 AF XY: 0.00145 AC XY: 108 AN XY: 74516

African (AFR) AF: 0.000313 AC: 13 AN: 41580

American (AMR) AF: 0.000261 AC: 4 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.000659 AC: 7 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00288 AC: 196 AN: 68022

Other (OTH) AF: 0.000947 AC: 2 AN: 2112

Alfa AF: 0.00209 Hom.: 1

Bravo AF: 0.00139

TwinsUK AF: 0.00270 AC: 10

ALSPAC AF: 0.00208 AC: 8

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00291 AC: 25

ExAC AF: 0.00152 AC: 185

EpiCase AF: 0.00229

EpiControl AF: 0.00261

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not provided (6)
-	-	2	MYH9-related disorder (2)
-	-	2	not specified (2)
-	-	1	Autosomal dominant nonsyndromic hearing loss 17 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	20
DANN	Benign	0.90
DEOGEN2	Benign	0.27	T
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.53
FATHMM_MKL	Benign	0.73	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.070	D
MetaRNN	Benign	0.010	T
MetaSVM	Benign	-0.62	T
MutationAssessor	Benign	0.81	L
PhyloP100		2.9
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-2.5	N
REVEL	Benign	0.23
Sift	Benign	0.053	T
Sift4G	Benign	0.51	T
Polyphen		0.0090	B
Vest4		0.27
MutPred		0.19		Gain of MoRF binding (P = 0.011)
MVP		0.76
MPC		0.64
ClinPred		0.016	T
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.098
gMVP		0.23
Mutation Taster		=94/6	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: rs140588099; hg19: chr22-36678779; COSMIC: COSV108032295; COSMIC: COSV108032295;