22-36281339-G-A

Position:

• chr22-36281339-G-A

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_002473.6(MYH9):​c.*1329C>T variant causes a 3 prime UTR change. The variant allele was found at a frequency of 0.00723 in 216,550 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 0.0075 (9 hom., cov: 32)
  • Exomes 𝑓: 0.0067 (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: 4.07

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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.33).
• BP6: Variant 22-36281339-G-A is Benign according to our data. Variant chr22-36281339-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 341458.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 = 0.00746 (1136/152324) while in subpopulation NFE AF= 0.00996 (678/68040). AF 95% confidence interval is 0.00934. There are 9 homozygotes in gnomad4. There are 629 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1136 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH9	NM_002473.6	c.*1329C>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.*1329C>T		3_prime_UTR_variant	41/41	1	NM_002473.6	P1

Frequencies

GnomAD3 genomes AF: 0.00747 AC: 1137 AN: 152206 Hom.: 9 Cov.: 32

Gnomad AFR AF: 0.000989

Gnomad AMI AF: 0.0143

Gnomad AMR AF: 0.00262

Gnomad ASJ AF: 0.0210

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.0259

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00996

Gnomad OTH AF: 0.00669

GnomAD4 exome AF: 0.00668 AC: 429 AN: 64226 Hom.: 1 Cov.: 0 AF XY: 0.00688 AC XY: 204 AN XY: 29630

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00325

Gnomad4 ASJ exome AF: 0.0200

Gnomad4 EAS exome AF: 0.000107

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0304

Gnomad4 NFE exome AF: 0.00743

Gnomad4 OTH exome AF: 0.00614

GnomAD4 genome AF: 0.00746 AC: 1136 AN: 152324 Hom.: 9 Cov.: 32 AF XY: 0.00845 AC XY: 629 AN XY: 74480

Gnomad4 AFR AF: 0.000986

Gnomad4 AMR AF: 0.00261

Gnomad4 ASJ AF: 0.0210

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.0259

Gnomad4 NFE AF: 0.00996

Gnomad4 OTH AF: 0.00662

Alfa AF: 0.0111 Hom.: 2

Bravo AF: 0.00510

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

CeGaT Center for Human Genetics Tuebingen

May 01, 2023

MYH9: BS2 -

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	-0.33
CADD	Benign	16
DANN	Benign	0.89
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: rs146582828; hg19: chr22-36677385;