chr22-36281868-A-G

Variant names:

• chr22-36281868-A-G
• rs7078
• NM_002473.6:c.*800T>C

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_002473.6(MYH9):​c.*800T>C variant causes a 3 prime UTR change. The variant allele was found at a frequency of 0.241 in 230,108 control chromosomes in the GnomAD database, including 7,389 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.23 (4507 hom., cov: 33)
  • Exomes 𝑓: 0.26 (2882 hom.)
• Consequence: MYH9 NM_002473.6 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 5.41
• Publications: 25 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: G2P, Labcorp Genetics (formerly Invitae)
• macrothrombocytopenia and granulocyte inclusions with or without nephritis or sensorineural hearing loss

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae), ClinGen
• 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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.37).
• BP6: Variant 22-36281868-A-G is Benign according to our data. Variant chr22-36281868-A-G is described in ClinVar as [Benign]. Clinvar id is 341469.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.291 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH9	NM_002473.6	c.*800T>C		3_prime_UTR_variant	Exon 41 of 41	ENST00000216181.11	NP_002464.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYH9	ENST00000216181.11	c.*800T>C		3_prime_UTR_variant	Exon 41 of 41	1	NM_002473.6	ENSP00000216181.6

Frequencies

GnomAD3 genomes AF: 0.233 AC: 35476 AN: 152104 Hom.: 4504 Cov.: 33

Gnomad AFR AF: 0.146

Gnomad AMI AF: 0.196

Gnomad AMR AF: 0.229

Gnomad ASJ AF: 0.325

Gnomad EAS AF: 0.0749

Gnomad SAS AF: 0.195

Gnomad FIN AF: 0.252

Gnomad MID AF: 0.285

Gnomad NFE AF: 0.295

Gnomad OTH AF: 0.231

GnomAD4 exome AF: 0.257 AC: 19978 AN: 77886 Hom.: 2882 Cov.: 0 AF XY: 0.258 AC XY: 9254 AN XY: 35910

African (AFR) AF: 0.149 AC: 546 AN: 3666

American (AMR) AF: 0.232 AC: 555 AN: 2396

Ashkenazi Jewish (ASJ) AF: 0.328 AC: 1602 AN: 4888

East Asian (EAS) AF: 0.0712 AC: 783 AN: 10998

South Asian (SAS) AF: 0.191 AC: 129 AN: 674

European-Finnish (FIN) AF: 0.246 AC: 118 AN: 480

Middle Eastern (MID) AF: 0.303 AC: 141 AN: 466

European-Non Finnish (NFE) AF: 0.300 AC: 14341 AN: 47842

Other (OTH) AF: 0.272 AC: 1763 AN: 6476

GnomAD4 genome AF: 0.233 AC: 35487 AN: 152222 Hom.: 4507 Cov.: 33 AF XY: 0.229 AC XY: 17034 AN XY: 74432

African (AFR) AF: 0.146 AC: 6081 AN: 41548

American (AMR) AF: 0.229 AC: 3500 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.325 AC: 1129 AN: 3470

East Asian (EAS) AF: 0.0747 AC: 388 AN: 5192

South Asian (SAS) AF: 0.195 AC: 942 AN: 4828

European-Finnish (FIN) AF: 0.252 AC: 2671 AN: 10602

Middle Eastern (MID) AF: 0.293 AC: 86 AN: 294

European-Non Finnish (NFE) AF: 0.295 AC: 20029 AN: 67966

Other (OTH) AF: 0.228 AC: 482 AN: 2114

Alfa AF: 0.257 Hom.: 2445

Bravo AF: 0.231

Asia WGS AF: 0.118 AC: 413 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal dominant nonsyndromic hearing loss 17 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

MYH9-related disorder Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.37
CADD	Benign	15
DANN	Benign	0.88
PhyloP100		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1
Mutation Taster		=100/0	polymorphism (auto)

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: rs7078; hg19: chr22-36677914; COSMIC: COSV53385097; COSMIC: COSV53385097;