22-36281507-TAAA-TAAAA

Variant names:

• chr22-36281507-T-TA
• rs56058205
• NM_002473.6:c.*1160dupT

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1 BS2

The NM_002473.6(MYH9):​c.*1160dupT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00807 in 205,504 control chromosomes in the GnomAD database, including 2 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0012 (1 hom., cov: 29)
  • Exomes 𝑓: 0.026 (1 hom.)
• Consequence: MYH9 NM_002473.6 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.216
• Publications: 2 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 -8 ACMG points.

• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00118 (175/147772) while in subpopulation EAS AF = 0.00693 (35/5054). AF 95% confidence interval is 0.00512. There are 1 homozygotes in GnomAd4. There are 85 alleles in the male GnomAd4 subpopulation. Median coverage is 29. This position passed quality control check.
• BS2: High AC in GnomAd4 at 175 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.*1160dupT		3_prime_UTR	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.*1160dupT		3_prime_UTR	Exon 41 of 41	ENSP00000216181.6	P35579-1
	MYH9	ENST00000685801.1		c.*1160dupT		3_prime_UTR	Exon 42 of 42	ENSP00000510688.1	A0A8I5KWT8
	MYH9	ENST00000955568.1		c.*1160dupT		3_prime_UTR	Exon 42 of 42	ENSP00000625627.1

Frequencies

GnomAD3 genomes AF: 0.00118 AC: 174 AN: 147706 Hom.: 1 Cov.: 29

Gnomad AFR AF: 0.000665

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00182

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00691

Gnomad SAS AF: 0.00149

Gnomad FIN AF: 0.000320

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00111

Gnomad OTH AF: 0.000498

GnomAD4 exome AF: 0.0257 AC: 1484 AN: 57732 Hom.: 1 Cov.: 0 AF XY: 0.0253 AC XY: 675 AN XY: 26678

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0160 AC: 47 AN: 2938

American (AMR) AF: 0.0293 AC: 51 AN: 1740

Ashkenazi Jewish (ASJ) AF: 0.0166 AC: 61 AN: 3668

East Asian (EAS) AF: 0.0526 AC: 410 AN: 7802

South Asian (SAS) AF: 0.0255 AC: 12 AN: 470

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 370

Middle Eastern (MID) AF: 0.0203 AC: 7 AN: 344

European-Non Finnish (NFE) AF: 0.0223 AC: 793 AN: 35502

Other (OTH) AF: 0.0210 AC: 103 AN: 4898

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00118 AC: 175 AN: 147772 Hom.: 1 Cov.: 29 AF XY: 0.00118 AC XY: 85 AN XY: 71914

African (AFR) AF: 0.000688 AC: 28 AN: 40714

American (AMR) AF: 0.00182 AC: 27 AN: 14822

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3420

East Asian (EAS) AF: 0.00693 AC: 35 AN: 5054

South Asian (SAS) AF: 0.00150 AC: 7 AN: 4674

European-Finnish (FIN) AF: 0.000320 AC: 3 AN: 9380

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 282

European-Non Finnish (NFE) AF: 0.00111 AC: 74 AN: 66510

Other (OTH) AF: 0.000494 AC: 1 AN: 2024

Alfa AF: 0.00 Hom.: 65

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.22
Mutation Taster		=100/0	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: rs56058205; hg19: chr22-36677553; COSMIC: COSV53390716; COSMIC: COSV53390716;