rs28409177

Variant names:

• chr22-36310226-T-C
• rs28409177
• NM_002473.6:c.1729-830A>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.1729-830A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.555 in 149,972 control chromosomes in the GnomAD database, including 25,877 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 0.56 (25877 hom., cov: 26)
• Consequence: MYH9 NM_002473.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.214
• Publications: 2 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=-0.94).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.703 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH9	NM_002473.6	c.1729-830A>G		intron_variant	Intron 14 of 40	ENST00000216181.11	NP_002464.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYH9	ENST00000216181.11	c.1729-830A>G		intron_variant	Intron 14 of 40	1	NM_002473.6	ENSP00000216181.6
MYH9	ENST00000685801.1	c.1729-830A>G		intron_variant	Intron 14 of 41			ENSP00000510688.1
MYH9	ENST00000691109.1	n.2024-830A>G		intron_variant	Intron 8 of 34
MYH9	ENST00000692930.1	n.1943-830A>G		intron_variant	Intron 14 of 14

Frequencies

GnomAD3 genomes AF: 0.556 AC: 83291 AN: 149866 Hom.: 25882 Cov.: 26

Gnomad AFR AF: 0.280

Gnomad AMI AF: 0.776

Gnomad AMR AF: 0.628

Gnomad ASJ AF: 0.542

Gnomad EAS AF: 0.277

Gnomad SAS AF: 0.459

Gnomad FIN AF: 0.700

Gnomad MID AF: 0.538

Gnomad NFE AF: 0.708

Gnomad OTH AF: 0.574

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

GnomAD4 genome AF: 0.555 AC: 83290 AN: 149972 Hom.: 25877 Cov.: 26 AF XY: 0.551 AC XY: 40294 AN XY: 73096

African (AFR) AF: 0.280 AC: 11395 AN: 40680

American (AMR) AF: 0.627 AC: 9470 AN: 15094

Ashkenazi Jewish (ASJ) AF: 0.542 AC: 1873 AN: 3458

East Asian (EAS) AF: 0.276 AC: 1395 AN: 5058

South Asian (SAS) AF: 0.460 AC: 2170 AN: 4718

European-Finnish (FIN) AF: 0.700 AC: 7061 AN: 10082

Middle Eastern (MID) AF: 0.537 AC: 158 AN: 294

European-Non Finnish (NFE) AF: 0.708 AC: 47878 AN: 67598

Other (OTH) AF: 0.569 AC: 1182 AN: 2078

Alfa AF: 0.616 Hom.: 4007

Bravo AF: 0.539

Asia WGS AF: 0.324 AC: 1127 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	3.6
DANN	Benign	0.49
PhyloP100		0.21
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: rs28409177; hg19: chr22-36706271;