22-36331506-G-T

Variant names:

• chr22-36331506-G-T
• rs8143119
• NM_002473.6:c.491-4018C>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002473.6(MYH9):​c.491-4018C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.481 in 151,982 control chromosomes in the GnomAD database, including 19,595 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.48 (19595 hom., cov: 32)
• Consequence: MYH9 NM_002473.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.521
• Publications: 4 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.593 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002473.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH9	NM_002473.6	MANE Select	c.491-4018C>A		intron	N/A	NP_002464.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH9	ENST00000216181.11	TSL:1 MANE Select	c.491-4018C>A		intron	N/A	ENSP00000216181.6
	MYH9	ENST00000401701.1	TSL:1	c.491-4018C>A		intron	N/A	ENSP00000384631.1
	MYH9	ENST00000685801.1		c.491-4018C>A		intron	N/A	ENSP00000510688.1

Frequencies

GnomAD3 genomes AF: 0.481 AC: 73109 AN: 151862 Hom.: 19595 Cov.: 32

Gnomad AFR AF: 0.267

Gnomad AMI AF: 0.686

Gnomad AMR AF: 0.581

Gnomad ASJ AF: 0.478

Gnomad EAS AF: 0.158

Gnomad SAS AF: 0.376

Gnomad FIN AF: 0.608

Gnomad MID AF: 0.601

Gnomad NFE AF: 0.598

Gnomad OTH AF: 0.506

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

GnomAD4 genome AF: 0.481 AC: 73117 AN: 151982 Hom.: 19595 Cov.: 32 AF XY: 0.480 AC XY: 35642 AN XY: 74288

African (AFR) AF: 0.267 AC: 11091 AN: 41498

American (AMR) AF: 0.580 AC: 8860 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.478 AC: 1657 AN: 3470

East Asian (EAS) AF: 0.158 AC: 818 AN: 5184

South Asian (SAS) AF: 0.377 AC: 1816 AN: 4816

European-Finnish (FIN) AF: 0.608 AC: 6402 AN: 10528

Middle Eastern (MID) AF: 0.592 AC: 174 AN: 294

European-Non Finnish (NFE) AF: 0.598 AC: 40618 AN: 67896

Other (OTH) AF: 0.501 AC: 1057 AN: 2108

Alfa AF: 0.551 Hom.: 75726

Bravo AF: 0.470

Asia WGS AF: 0.251 AC: 876 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	7.6
DANN	Benign	0.87
PhyloP100		0.52
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs8143119; hg19: chr22-36727551;