rs12107

chr22-36281936-G-Achr22-36281936-G-Cchr22-36281936-G-T

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.*732C>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 0.182 in 231,954 control chromosomes in the GnomAD database, including 6,244 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (3053 hom., cov: 34)
  • Exomes 𝑓: 0.21 (3191 hom.)
• Consequence: MYH9 NM_002473.6 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.965

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=-0.91).
• BP6: Variant 22-36281936-G-A is Benign according to our data. Variant chr22-36281936-G-A is described in ClinVar as [Benign]. Clinvar id is 341471.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.*732C>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.*732C>T		3_prime_UTR_variant	41/41	1	NM_002473.6	P1

Frequencies

GnomAD3 genomes AF: 0.166 AC: 25224 AN: 152174 Hom.: 3035 Cov.: 34

Gnomad AFR AF: 0.105

Gnomad AMI AF: 0.133

Gnomad AMR AF: 0.191

Gnomad ASJ AF: 0.145

Gnomad EAS AF: 0.670

Gnomad SAS AF: 0.412

Gnomad FIN AF: 0.202

Gnomad MID AF: 0.104

Gnomad NFE AF: 0.137

Gnomad OTH AF: 0.177

GnomAD4 exome AF: 0.212 AC: 16898 AN: 79662 Hom.: 3191 Cov.: 0 AF XY: 0.211 AC XY: 7730 AN XY: 36722

Gnomad4 AFR exome AF: 0.101

Gnomad4 AMR exome AF: 0.198

Gnomad4 ASJ exome AF: 0.153

Gnomad4 EAS exome AF: 0.659

Gnomad4 SAS exome AF: 0.433

Gnomad4 FIN exome AF: 0.190

Gnomad4 NFE exome AF: 0.130

Gnomad4 OTH exome AF: 0.165

GnomAD4 genome AF: 0.166 AC: 25268 AN: 152292 Hom.: 3053 Cov.: 34 AF XY: 0.177 AC XY: 13196 AN XY: 74480

Gnomad4 AFR AF: 0.105

Gnomad4 AMR AF: 0.192

Gnomad4 ASJ AF: 0.145

Gnomad4 EAS AF: 0.671

Gnomad4 SAS AF: 0.411

Gnomad4 FIN AF: 0.202

Gnomad4 NFE AF: 0.137

Gnomad4 OTH AF: 0.187

Alfa AF: 0.0654 Hom.: 83

Bravo AF: 0.158

Asia WGS AF: 0.561 AC: 1947 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

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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Oct 29, 2020

This variant is associated with the following publications: (PMID: 29207917) -

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	-0.91
Cadd	Benign	0.43
Dann	Benign	0.58

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: rs12107; hg19: chr22-36677982;