NM_002473.6:c.5766-227A>G

Variant names:

• chr22-36283012-T-C
• rs735854
• NM_002473.6:c.5766-227A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_002473.6(MYH9):​c.5766-227A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.526 in 152,068 control chromosomes in the GnomAD database, including 24,215 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.53 (24215 hom., cov: 32)
• Consequence: MYH9 NM_002473.6 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0100
• Publications: 25 publications found

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]

MYH9 Gene-Disease associations (from GenCC):

• autosomal dominant nonsyndromic hearing loss 17

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• macrothrombocytopenia and granulocyte inclusions with or without nephritis or sensorineural hearing loss

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae), ClinGen
• May-Hegglin anomaly

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• autosomal dominant nonsyndromic hearing loss

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 22-36283012-T-C is Benign according to our data. Variant chr22-36283012-T-C is described in ClinVar as [Benign]. Clinvar id is 1239899.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.777 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH9	NM_002473.6	c.5766-227A>G		intron_variant	Intron 40 of 40	ENST00000216181.11	NP_002464.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYH9	ENST00000216181.11	c.5766-227A>G		intron_variant	Intron 40 of 40	1	NM_002473.6	ENSP00000216181.6

Frequencies

GnomAD3 genomes AF: 0.527 AC: 80009 AN: 151950 Hom.: 24194 Cov.: 32

Gnomad AFR AF: 0.207

Gnomad AMI AF: 0.779

Gnomad AMR AF: 0.646

Gnomad ASJ AF: 0.558

Gnomad EAS AF: 0.796

Gnomad SAS AF: 0.649

Gnomad FIN AF: 0.674

Gnomad MID AF: 0.516

Gnomad NFE AF: 0.636

Gnomad OTH AF: 0.566

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.526 AC: 80041 AN: 152068 Hom.: 24215 Cov.: 32 AF XY: 0.536 AC XY: 39816 AN XY: 74330

African (AFR) AF: 0.207 AC: 8570 AN: 41480

American (AMR) AF: 0.646 AC: 9891 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.558 AC: 1939 AN: 3472

East Asian (EAS) AF: 0.797 AC: 4108 AN: 5152

South Asian (SAS) AF: 0.649 AC: 3124 AN: 4812

European-Finnish (FIN) AF: 0.674 AC: 7122 AN: 10570

Middle Eastern (MID) AF: 0.517 AC: 152 AN: 294

European-Non Finnish (NFE) AF: 0.636 AC: 43221 AN: 67966

Other (OTH) AF: 0.572 AC: 1210 AN: 2116

Alfa AF: 0.601 Hom.: 101802

Bravo AF: 0.508

Asia WGS AF: 0.717 AC: 2492 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jun 29, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	2.1
DANN	Benign	0.41
PhyloP100		-0.010
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs735854; hg19: chr22-36679058;