rs5756157

Variant names:

• chr22-36327652-T-G
• rs5756157
• NM_002473.6:c.491-164A>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002473.6(MYH9):​c.491-164A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.548 in 151,990 control chromosomes in the GnomAD database, including 24,448 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency: Genomes: 𝑓 0.55 (24448 hom., cov: 31)
• Consequence: MYH9 NM_002473.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.23
• Publications: 6 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 22-36327652-T-G is Benign according to our data. Variant chr22-36327652-T-G is described in ClinVar as Benign. ClinVar VariationId is 1262804.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.653 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH9	NM_002473.6	c.491-164A>C		intron_variant	Intron 3 of 40	ENST00000216181.11	NP_002464.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYH9	ENST00000216181.11	c.491-164A>C		intron_variant	Intron 3 of 40	1	NM_002473.6	ENSP00000216181.6

Frequencies

GnomAD3 genomes AF: 0.548 AC: 83239 AN: 151872 Hom.: 24441 Cov.: 31

Gnomad AFR AF: 0.372

Gnomad AMI AF: 0.769

Gnomad AMR AF: 0.639

Gnomad ASJ AF: 0.535

Gnomad EAS AF: 0.160

Gnomad SAS AF: 0.396

Gnomad FIN AF: 0.636

Gnomad MID AF: 0.633

Gnomad NFE AF: 0.658

Gnomad OTH AF: 0.569

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

GnomAD4 genome AF: 0.548 AC: 83278 AN: 151990 Hom.: 24448 Cov.: 31 AF XY: 0.544 AC XY: 40399 AN XY: 74280

African (AFR) AF: 0.372 AC: 15433 AN: 41452

American (AMR) AF: 0.639 AC: 9752 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.535 AC: 1856 AN: 3466

East Asian (EAS) AF: 0.159 AC: 822 AN: 5162

South Asian (SAS) AF: 0.397 AC: 1913 AN: 4816

European-Finnish (FIN) AF: 0.636 AC: 6711 AN: 10548

Middle Eastern (MID) AF: 0.626 AC: 184 AN: 294

European-Non Finnish (NFE) AF: 0.658 AC: 44715 AN: 67958

Other (OTH) AF: 0.564 AC: 1191 AN: 2112

Alfa AF: 0.601 Hom.: 43670

Bravo AF: 0.543

Asia WGS AF: 0.269 AC: 939 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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	-0.91
CADD	Benign	0.41
DANN	Benign	0.45
PhyloP100		-1.2
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs5756157; hg19: chr22-36723697;