chr22-36281982-G-A

Position:

• chr22-36281982-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_002473.6(MYH9):​c.*686C>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 0.00711 in 233,722 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0074 (9 hom., cov: 33)
  • Exomes 𝑓: 0.0066 (1 hom.)
• Consequence: MYH9 NM_002473.6 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.126

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=-0.73).
• BP6: Variant 22-36281982-G-A is Benign according to our data. Variant chr22-36281982-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 341472.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00739 (1126/152404) while in subpopulation NFE AF= 0.00985 (670/68038). AF 95% confidence interval is 0.00923. There are 9 homozygotes in gnomad4. There are 625 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1126 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH9	NM_002473.6	c.*686C>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.*686C>T		3_prime_UTR_variant	41/41	1	NM_002473.6	P1

Frequencies

GnomAD3 genomes AF: 0.00740 AC: 1127 AN: 152286 Hom.: 9 Cov.: 33

Gnomad AFR AF: 0.000964

Gnomad AMI AF: 0.0143

Gnomad AMR AF: 0.00248

Gnomad ASJ AF: 0.0210

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.0260

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00985

Gnomad OTH AF: 0.00669

GnomAD4 exome AF: 0.00658 AC: 535 AN: 81318 Hom.: 1 Cov.: 0 AF XY: 0.00648 AC XY: 243 AN XY: 37524

Gnomad4 AFR exome AF: 0.000261

Gnomad4 AMR exome AF: 0.00271

Gnomad4 ASJ exome AF: 0.0201

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0286

Gnomad4 NFE exome AF: 0.00738

Gnomad4 OTH exome AF: 0.00566

GnomAD4 genome AF: 0.00739 AC: 1126 AN: 152404 Hom.: 9 Cov.: 33 AF XY: 0.00839 AC XY: 625 AN XY: 74530

Gnomad4 AFR AF: 0.000961

Gnomad4 AMR AF: 0.00248

Gnomad4 ASJ AF: 0.0210

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.0260

Gnomad4 NFE AF: 0.00985

Gnomad4 OTH AF: 0.00662

Alfa AF: 0.0113 Hom.: 2

Bravo AF: 0.00505

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal dominant nonsyndromic hearing loss 17 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

May 14, 2021

- -

MYH9-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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	-0.73
CADD	Benign	10
DANN	Benign	0.83

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: rs55994070; hg19: chr22-36678028;