chr22-36314138-T-C

Variant names:

• chr22-36314138-T-C
• rs3752462
• NM_002473.6:c.1554+7A>G

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.1554+7A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.621 in 1,613,278 control chromosomes in the GnomAD database, including 324,968 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.53 (23800 hom., cov: 32)
  • Exomes 𝑓: 0.63 (301168 hom.)
• Consequence: MYH9 NM_002473.6 splice_region, intron
• Scores: Splicing: ADA: 0.00002338
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -0.149

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=-0.82).
• BP6: Variant 22-36314138-T-C is Benign according to our data. Variant chr22-36314138-T-C is described in ClinVar as [Benign]. Clinvar id is 44550.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-36314138-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.671 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH9	NM_002473.6	c.1554+7A>G		splice_region_variant, intron_variant	Intron 13 of 40	ENST00000216181.11	NP_002464.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYH9	ENST00000216181.11	c.1554+7A>G		splice_region_variant, intron_variant	Intron 13 of 40	1	NM_002473.6	ENSP00000216181.6

Frequencies

GnomAD3 genomes AF: 0.528 AC: 80197 AN: 152024 Hom.: 23805 Cov.: 32

Gnomad AFR AF: 0.270

Gnomad AMI AF: 0.761

Gnomad AMR AF: 0.612

Gnomad ASJ AF: 0.528

Gnomad EAS AF: 0.223

Gnomad SAS AF: 0.384

Gnomad FIN AF: 0.652

Gnomad MID AF: 0.516

Gnomad NFE AF: 0.676

Gnomad OTH AF: 0.549

GnomAD3 exomes AF: 0.565 AC: 142047 AN: 251232 Hom.: 43403 AF XY: 0.565 AC XY: 76722 AN XY: 135824

Gnomad AFR exome AF: 0.256

Gnomad AMR exome AF: 0.630

Gnomad ASJ exome AF: 0.532

Gnomad EAS exome AF: 0.218

Gnomad SAS exome AF: 0.404

Gnomad FIN exome AF: 0.653

Gnomad NFE exome AF: 0.674

Gnomad OTH exome AF: 0.607

GnomAD4 exome AF: 0.631 AC: 921801 AN: 1461136 Hom.: 301168 Cov.: 58 AF XY: 0.625 AC XY: 454592 AN XY: 726894

Gnomad4 AFR exome AF: 0.252

Gnomad4 AMR exome AF: 0.631

Gnomad4 ASJ exome AF: 0.527

Gnomad4 EAS exome AF: 0.219

Gnomad4 SAS exome AF: 0.412

Gnomad4 FIN exome AF: 0.655

Gnomad4 NFE exome AF: 0.678

Gnomad4 OTH exome AF: 0.586

GnomAD4 genome AF: 0.527 AC: 80198 AN: 152142 Hom.: 23800 Cov.: 32 AF XY: 0.523 AC XY: 38874 AN XY: 74376

Gnomad4 AFR AF: 0.269

Gnomad4 AMR AF: 0.611

Gnomad4 ASJ AF: 0.528

Gnomad4 EAS AF: 0.222

Gnomad4 SAS AF: 0.385

Gnomad4 FIN AF: 0.652

Gnomad4 NFE AF: 0.676

Gnomad4 OTH AF: 0.544

Alfa AF: 0.635 Hom.: 61378

Bravo AF: 0.515

Asia WGS AF: 0.255 AC: 889 AN: 3478

EpiCase AF: 0.665

EpiControl AF: 0.663

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 07, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 15, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 89% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 83. Only high quality variants are reported. -

May 09, 2017

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided Benign:3

Nov 27, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal dominant nonsyndromic hearing loss 17 Benign:2

Jan 12, 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. -

Sep 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Macrothrombocytopenia and granulocyte inclusions with or without nephritis or sensorineural hearing loss Benign:1

Sep 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

MYH9-related disorder Benign:1

Jan 12, 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	-0.82
CADD	Benign	5.5
DANN	Benign	0.56
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000023
dbscSNV1_RF	Benign	0.0
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: rs3752462; hg19: chr22-36710183;