chr22-36281354-G-A

Position:

• chr22-36281354-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002473.6(MYH9):​c.*1314C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.18 in 219,204 control chromosomes in the GnomAD database, including 5,782 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (3057 hom., cov: 33)
  • Exomes 𝑓: 0.21 (2725 hom.)
• Consequence: MYH9 NM_002473.6 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 2.65

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BP6: Variant 22-36281354-G-A is Benign according to our data. Variant chr22-36281354-G-A is described in ClinVar as [Benign]. Clinvar id is 341459.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.652 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH9	NM_002473.6	c.*1314C>T		3_prime_UTR_variant	41/41	ENST00000216181.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH9	ENST00000216181.11	c.*1314C>T		3_prime_UTR_variant	41/41	1	NM_002473.6	P1

Frequencies

GnomAD3 genomes AF: 0.166 AC: 25197 AN: 152106 Hom.: 3039 Cov.: 33

Gnomad AFR AF: 0.105

Gnomad AMI AF: 0.133

Gnomad AMR AF: 0.190

Gnomad ASJ AF: 0.145

Gnomad EAS AF: 0.669

Gnomad SAS AF: 0.412

Gnomad FIN AF: 0.202

Gnomad MID AF: 0.104

Gnomad NFE AF: 0.137

Gnomad OTH AF: 0.178

GnomAD4 exome AF: 0.213 AC: 14264 AN: 66980 Hom.: 2725 Cov.: 0 AF XY: 0.212 AC XY: 6537 AN XY: 30872

Gnomad4 AFR exome AF: 0.0979

Gnomad4 AMR exome AF: 0.194

Gnomad4 ASJ exome AF: 0.149

Gnomad4 EAS exome AF: 0.659

Gnomad4 SAS exome AF: 0.448

Gnomad4 FIN exome AF: 0.190

Gnomad4 NFE exome AF: 0.129

Gnomad4 OTH exome AF: 0.162

GnomAD4 genome AF: 0.166 AC: 25242 AN: 152224 Hom.: 3057 Cov.: 33 AF XY: 0.177 AC XY: 13175 AN XY: 74418

Gnomad4 AFR AF: 0.105

Gnomad4 AMR AF: 0.191

Gnomad4 ASJ AF: 0.145

Gnomad4 EAS AF: 0.670

Gnomad4 SAS AF: 0.411

Gnomad4 FIN AF: 0.202

Gnomad4 NFE AF: 0.137

Gnomad4 OTH AF: 0.187

Alfa AF: 0.149 Hom.: 3698

Bravo AF: 0.158

Asia WGS AF: 0.563 AC: 1955 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

Autosomal dominant nonsyndromic hearing loss 17 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

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. -

MYH9-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

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	-0.50
CADD	Benign	14
DANN	Benign	0.79
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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

Publications

LitVar

Other links and lift over

dbSNP: rs2481; hg19: chr22-36677400;