chr22-36317486-T-C

Variant names:

• chr22-36317486-T-C
• rs9610489
• NM_002473.6:c.1227+721A>G

Variant summary

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

The NM_002473.6(MYH9):​c.1227+721A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.231 in 152,140 control chromosomes in the GnomAD database, including 4,896 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 0.23 (4896 hom., cov: 32)
• Consequence: MYH9 NM_002473.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.231
• Publications: 11 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=-0.9).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.687 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.1227+721A>G		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.1227+721A>G		intron	N/A	ENSP00000216181.6
	MYH9	ENST00000687820.1		n.872A>G		non_coding_transcript_exon	Exon 2 of 2
	MYH9	ENST00000685801.1		c.1227+721A>G		intron	N/A	ENSP00000510688.1

Frequencies

GnomAD3 genomes AF: 0.231 AC: 35065 AN: 152022 Hom.: 4875 Cov.: 32

Gnomad AFR AF: 0.187

Gnomad AMI AF: 0.130

Gnomad AMR AF: 0.282

Gnomad ASJ AF: 0.327

Gnomad EAS AF: 0.705

Gnomad SAS AF: 0.483

Gnomad FIN AF: 0.156

Gnomad MID AF: 0.329

Gnomad NFE AF: 0.199

Gnomad OTH AF: 0.245

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

GnomAD4 genome AF: 0.231 AC: 35107 AN: 152140 Hom.: 4896 Cov.: 32 AF XY: 0.238 AC XY: 17741 AN XY: 74408

African (AFR) AF: 0.187 AC: 7748 AN: 41496

American (AMR) AF: 0.283 AC: 4326 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.327 AC: 1133 AN: 3470

East Asian (EAS) AF: 0.706 AC: 3649 AN: 5166

South Asian (SAS) AF: 0.482 AC: 2324 AN: 4826

European-Finnish (FIN) AF: 0.156 AC: 1651 AN: 10598

Middle Eastern (MID) AF: 0.340 AC: 100 AN: 294

European-Non Finnish (NFE) AF: 0.199 AC: 13526 AN: 67982

Other (OTH) AF: 0.251 AC: 531 AN: 2112

Alfa AF: 0.215 Hom.: 7587

Bravo AF: 0.235

Asia WGS AF: 0.563 AC: 1956 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	2.1
DANN	Benign	0.30
PhyloP100		-0.23
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: rs9610489; hg19: chr22-36713531;