NM_002473.6:c.1083C>T

Variant names:

• chr22-36319565-G-A
• rs56001030
• NM_002473.6:c.1083C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_002473.6(MYH9):​c.1083C>T​(p.Asp361Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00448 in 1,614,138 control chromosomes in the GnomAD database, including 39 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0042 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0045 (36 hom.)
• Consequence: MYH9 NM_002473.6 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: 2.54
• Publications: 4 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant 22-36319565-G-A is Benign according to our data. Variant chr22-36319565-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 44548.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.55 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00422 (642/152266) while in subpopulation AMR AF = 0.0116 (178/15292). AF 95% confidence interval is 0.0102. There are 3 homozygotes in GnomAd4. There are 309 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 642 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.1083C>T	p.Asp361Asp	synonymous	Exon 10 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.1083C>T	p.Asp361Asp	synonymous	Exon 10 of 41	ENSP00000216181.6	P35579-1
	MYH9	ENST00000685801.1		c.1083C>T	p.Asp361Asp	synonymous	Exon 10 of 42	ENSP00000510688.1	A0A8I5KWT8
	MYH9	ENST00000955568.1		c.1083C>T	p.Asp361Asp	synonymous	Exon 10 of 42	ENSP00000625627.1

Frequencies

GnomAD3 genomes AF: 0.00422 AC: 642 AN: 152148 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.000918

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0117

Gnomad ASJ AF: 0.0317

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00412

Gnomad OTH AF: 0.00717

GnomAD2 exomes AF: 0.00464 AC: 1166 AN: 251438 AF XY: 0.00438

Gnomad AFR exome AF: 0.000923

Gnomad AMR exome AF: 0.00928

Gnomad ASJ exome AF: 0.0266

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00120

Gnomad NFE exome AF: 0.00443

Gnomad OTH exome AF: 0.00505

GnomAD4 exome AF: 0.00450 AC: 6585 AN: 1461872 Hom.: 36 Cov.: 32 AF XY: 0.00447 AC XY: 3250 AN XY: 727236

African (AFR) AF: 0.000807 AC: 27 AN: 33478

American (AMR) AF: 0.00912 AC: 408 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0267 AC: 697 AN: 26136

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

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

European-Finnish (FIN) AF: 0.000730 AC: 39 AN: 53416

Middle Eastern (MID) AF: 0.00121 AC: 7 AN: 5768

European-Non Finnish (NFE) AF: 0.00455 AC: 5065 AN: 1111998

Other (OTH) AF: 0.00566 AC: 342 AN: 60394

GnomAD4 genome AF: 0.00422 AC: 642 AN: 152266 Hom.: 3 Cov.: 32 AF XY: 0.00415 AC XY: 309 AN XY: 74466

African (AFR) AF: 0.000915 AC: 38 AN: 41536

American (AMR) AF: 0.0116 AC: 178 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0317 AC: 110 AN: 3472

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

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4808

European-Finnish (FIN) AF: 0.00188 AC: 20 AN: 10620

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

European-Non Finnish (NFE) AF: 0.00412 AC: 280 AN: 68030

Other (OTH) AF: 0.00710 AC: 15 AN: 2114

Alfa AF: 0.00503 Hom.: 2

Bravo AF: 0.00534

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00632

EpiControl AF: 0.00522

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (8)
-	-	4	not provided (4)
-	-	1	Atypical hemolytic-uremic syndrome (1)
-	-	1	Autosomal dominant nonsyndromic hearing loss 17 (1)
-	-	1	MYH9-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	13
DANN	Benign	0.86
PhyloP100		2.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
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: rs56001030; hg19: chr22-36715610; COSMIC: COSV53384826;