NM_002473.6:c.5815G>A

Variant names:

• chr22-36282736-C-T
• rs115031369
• NM_002473.6:c.5815G>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.5815G>A​(p.Ala1939Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00124 in 1,613,790 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A1939A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0047 (10 hom., cov: 33)
  • Exomes 𝑓: 0.00089 (9 hom.)
• Consequence: MYH9 NM_002473.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.637
• Publications: 8 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=0.0027503371).
• BP6: Variant 22-36282736-C-T is Benign according to our data. Variant chr22-36282736-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 178424.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00466 (710/152366) while in subpopulation AFR AF = 0.0157 (654/41588). AF 95% confidence interval is 0.0147. There are 10 homozygotes in GnomAd4. There are 329 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 710 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.5815G>A	p.Ala1939Thr	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.5815G>A	p.Ala1939Thr	missense	Exon 41 of 41	ENSP00000216181.6	P35579-1
	MYH9	ENST00000685801.1		c.5878G>A	p.Ala1960Thr	missense	Exon 42 of 42	ENSP00000510688.1	A0A8I5KWT8
	MYH9	ENST00000955568.1		c.5878G>A	p.Ala1960Thr	missense	Exon 42 of 42	ENSP00000625627.1

Frequencies

GnomAD3 genomes AF: 0.00465 AC: 708 AN: 152248 Hom.: 10 Cov.: 33

Gnomad AFR AF: 0.0157

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00150

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000441

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.00121 AC: 303 AN: 250892 AF XY: 0.000885

Gnomad AFR exome AF: 0.0151

Gnomad AMR exome AF: 0.000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000291

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000887 AC: 1297 AN: 1461424 Hom.: 9 Cov.: 31 AF XY: 0.000824 AC XY: 599 AN XY: 727012

African (AFR) AF: 0.0168 AC: 561 AN: 33478

American (AMR) AF: 0.000850 AC: 38 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

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

South Asian (SAS) AF: 0.000128 AC: 11 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52968

Middle Eastern (MID) AF: 0.00156 AC: 9 AN: 5768

European-Non Finnish (NFE) AF: 0.000483 AC: 537 AN: 1112002

Other (OTH) AF: 0.00233 AC: 141 AN: 60392

GnomAD4 genome AF: 0.00466 AC: 710 AN: 152366 Hom.: 10 Cov.: 33 AF XY: 0.00441 AC XY: 329 AN XY: 74522

African (AFR) AF: 0.0157 AC: 654 AN: 41588

American (AMR) AF: 0.00150 AC: 23 AN: 15310

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

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

European-Non Finnish (NFE) AF: 0.000441 AC: 30 AN: 68026

Other (OTH) AF: 0.00142 AC: 3 AN: 2110

Alfa AF: 0.00207 Hom.: 7

Bravo AF: 0.00532

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.0143 AC: 63

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.00143 AC: 173

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.000654

EpiControl AF: 0.000296

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	0.29
DANN	Benign	0.79
DEOGEN2	Benign	0.18	T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.040	N
LIST_S2	Benign	0.60	T
MetaRNN	Benign	0.0028	T
MetaSVM	Benign	-0.76	T
MutationAssessor	Benign	0.55	N
PhyloP100		-0.64
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.18	N
REVEL	Benign	0.23
Sift	Benign	0.39	T
Sift4G	Benign	0.50	T
Polyphen		0.0	B
Vest4		0.019
MVP		0.40
MPC		0.49
ClinPred		0.0023	T
GERP RS		-8.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.013
gMVP		0.072
Mutation Taster		=98/2	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: rs115031369; hg19: chr22-36678782; COSMIC: COSV99340280; COSMIC: COSV99340280;