NM_002473.6:c.5483+4C>G

Variant names:

• chr22-36285117-G-C
• rs56327920
• NM_002473.6:c.5483+4C>G

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.5483+4C>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 0.02 in 1,613,594 control chromosomes in the GnomAD database, including 387 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 0.015 (26 hom., cov: 33)
  • Exomes 𝑓: 0.021 (361 hom.)
• Consequence: MYH9 NM_002473.6 splice_region, intron
• Scores: Splicing: ADA: 0.0002236
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -1.31

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=-0.71).
• BP6: Variant 22-36285117-G-C is Benign according to our data. Variant chr22-36285117-G-C is described in ClinVar as [Benign]. Clinvar id is 44570.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-36285117-G-C is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0152 (2309/152352) while in subpopulation NFE AF= 0.0224 (1524/68026). AF 95% confidence interval is 0.0215. There are 26 homozygotes in gnomad4. There are 1095 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 2309 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH9	NM_002473.6	c.5483+4C>G		splice_region_variant, intron_variant	Intron 38 of 40	ENST00000216181.11	NP_002464.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYH9	ENST00000216181.11	c.5483+4C>G		splice_region_variant, intron_variant	Intron 38 of 40	1	NM_002473.6	ENSP00000216181.6

Frequencies

GnomAD3 genomes AF: 0.0152 AC: 2310 AN: 152234 Hom.: 26 Cov.: 33

Gnomad AFR AF: 0.00412

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.00988

Gnomad ASJ AF: 0.0118

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.0355

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0224

Gnomad OTH AF: 0.0124

GnomAD3 exomes AF: 0.0158 AC: 3933 AN: 249710 Hom.: 57 AF XY: 0.0158 AC XY: 2133 AN XY: 135078

Gnomad AFR exome AF: 0.00308

Gnomad AMR exome AF: 0.00478

Gnomad ASJ exome AF: 0.0158

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00310

Gnomad FIN exome AF: 0.0312

Gnomad NFE exome AF: 0.0239

Gnomad OTH exome AF: 0.0170

GnomAD4 exome AF: 0.0205 AC: 30014 AN: 1461242 Hom.: 361 Cov.: 32 AF XY: 0.0200 AC XY: 14564 AN XY: 726922

Gnomad4 AFR exome AF: 0.00260

Gnomad4 AMR exome AF: 0.00510

Gnomad4 ASJ exome AF: 0.0143

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00353

Gnomad4 FIN exome AF: 0.0331

Gnomad4 NFE exome AF: 0.0235

Gnomad4 OTH exome AF: 0.0188

GnomAD4 genome AF: 0.0152 AC: 2309 AN: 152352 Hom.: 26 Cov.: 33 AF XY: 0.0147 AC XY: 1095 AN XY: 74496

Gnomad4 AFR AF: 0.00414

Gnomad4 AMR AF: 0.00986

Gnomad4 ASJ AF: 0.0118

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00207

Gnomad4 FIN AF: 0.0355

Gnomad4 NFE AF: 0.0224

Gnomad4 OTH AF: 0.0123

Alfa AF: 0.00957 Hom.: 4

Bravo AF: 0.0139

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.0190

EpiControl AF: 0.0191

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jun 06, 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. -

-

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

5483+4C>G in Intron 38 of MYH9: This variant is not expected to have clinical si gnificance because it has been identified in 2.3% (163/7020) of European America n chromosomes from a broad population by the NHLBI Exome Sequencing Project (htt p://evs.gs.washington.edu/EVS; dbSNP rs56327920). -

not provided Benign:4

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Aug 12, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 20, 2018

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 02, 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:1

Jan 13, 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. -

Kidney disorder Benign:1

Nov 16, 2021

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

MYH9-related disorder Benign:1

Jan 13, 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	-0.71
CADD	Benign	0.26
DANN	Benign	0.76

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00022
dbscSNV1_RF	Benign	0.042
SpliceAI score (max)		0.040		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: rs56327920; hg19: chr22-36681163; COSMIC: COSV53388011; COSMIC: COSV53388011;