NM_002473.6:c.1843+287G>A

Variant names:

• chr22-36308995-C-T
• rs2239781
• NM_002473.6:c.1843+287G>A

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.1843+287G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.198 in 427,364 control chromosomes in the GnomAD database, including 10,300 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.20 (3977 hom., cov: 33)
  • Exomes 𝑓: 0.20 (6323 hom.)
• Consequence: MYH9 NM_002473.6 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.585
• Publications: 10 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=-0.86).
• BP6: Variant 22-36308995-C-T is Benign according to our data. Variant chr22-36308995-C-T is described in ClinVar as Benign. ClinVar VariationId is 1276781.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.608 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.1843+287G>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.1843+287G>A		intron	N/A	ENSP00000216181.6
	MYH9	ENST00000692930.1		n.2344G>A		non_coding_transcript_exon	Exon 15 of 15
	MYH9	ENST00000685801.1		c.1844-125G>A		intron	N/A	ENSP00000510688.1

Frequencies

GnomAD3 genomes AF: 0.195 AC: 29698 AN: 152012 Hom.: 3963 Cov.: 33

Gnomad AFR AF: 0.0654

Gnomad AMI AF: 0.184

Gnomad AMR AF: 0.252

Gnomad ASJ AF: 0.351

Gnomad EAS AF: 0.625

Gnomad SAS AF: 0.446

Gnomad FIN AF: 0.194

Gnomad MID AF: 0.263

Gnomad NFE AF: 0.203

Gnomad OTH AF: 0.223

GnomAD4 exome AF: 0.199 AC: 54800 AN: 275234 Hom.: 6323 AF XY: 0.200 AC XY: 26174 AN XY: 130574

African (AFR) AF: 0.0440 AC: 224 AN: 5086

American (AMR) AF: 0.227 AC: 70 AN: 308

Ashkenazi Jewish (ASJ) AF: 0.345 AC: 585 AN: 1696

East Asian (EAS) AF: 0.612 AC: 683 AN: 1116

South Asian (SAS) AF: 0.416 AC: 2220 AN: 5336

European-Finnish (FIN) AF: 0.107 AC: 9 AN: 84

Middle Eastern (MID) AF: 0.288 AC: 156 AN: 542

European-Non Finnish (NFE) AF: 0.193 AC: 48666 AN: 252106

Other (OTH) AF: 0.244 AC: 2187 AN: 8960

GnomAD4 genome AF: 0.195 AC: 29734 AN: 152130 Hom.: 3977 Cov.: 33 AF XY: 0.203 AC XY: 15131 AN XY: 74370

African (AFR) AF: 0.0654 AC: 2715 AN: 41532

American (AMR) AF: 0.252 AC: 3860 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.351 AC: 1216 AN: 3466

East Asian (EAS) AF: 0.627 AC: 3234 AN: 5162

South Asian (SAS) AF: 0.445 AC: 2145 AN: 4816

European-Finnish (FIN) AF: 0.194 AC: 2053 AN: 10584

Middle Eastern (MID) AF: 0.269 AC: 79 AN: 294

European-Non Finnish (NFE) AF: 0.203 AC: 13781 AN: 67964

Other (OTH) AF: 0.229 AC: 483 AN: 2112

Alfa AF: 0.201 Hom.: 7368

Bravo AF: 0.193

Asia WGS AF: 0.529 AC: 1837 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	1.3
DANN	Benign	0.84
PhyloP100		-0.58
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: rs2239781; hg19: chr22-36705041;