rs56020676

Variant names:

• chr22-36294074-T-C
• rs56020676
• NM_002473.6:c.3837+18A>G

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.3837+18A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0263 in 1,605,878 control chromosomes in the GnomAD database, including 3,285 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.087 (1599 hom., cov: 33)
  • Exomes 𝑓: 0.020 (1686 hom.)
• Consequence: MYH9 NM_002473.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.775
• Publications: 1 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: Labcorp Genetics (formerly Invitae), G2P
• macrothrombocytopenia and granulocyte inclusions with or without nephritis or sensorineural hearing loss

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, ClinGen, Labcorp Genetics (formerly Invitae), Orphanet
• 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=-0.81).
• BP6: Variant 22-36294074-T-C is Benign according to our data. Variant chr22-36294074-T-C is described in ClinVar as Benign. ClinVar VariationId is 258744.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.269 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH9	NM_002473.6	MANE Select	c.3837+18A>G		intron	N/A	NP_002464.1	P35579-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH9	ENST00000216181.11	TSL:1 MANE Select	c.3837+18A>G		intron	N/A	ENSP00000216181.6	P35579-1
	MYH9	ENST00000685801.1		c.3900+18A>G		intron	N/A	ENSP00000510688.1	A0A8I5KWT8
	MYH9	ENST00000955568.1		c.3900+18A>G		intron	N/A	ENSP00000625627.1

Frequencies

GnomAD3 genomes AF: 0.0873 AC: 13281 AN: 152062 Hom.: 1596 Cov.: 33

Gnomad AFR AF: 0.274

Gnomad AMI AF: 0.0175

Gnomad AMR AF: 0.0395

Gnomad ASJ AF: 0.0211

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00870

Gnomad FIN AF: 0.0184

Gnomad MID AF: 0.0728

Gnomad NFE AF: 0.0130

Gnomad OTH AF: 0.0589

GnomAD2 exomes AF: 0.0312 AC: 7610 AN: 244238 AF XY: 0.0259

Gnomad AFR exome AF: 0.279

Gnomad AMR exome AF: 0.0217

Gnomad ASJ exome AF: 0.0201

Gnomad EAS exome AF: 0.0000545

Gnomad FIN exome AF: 0.0186

Gnomad NFE exome AF: 0.0128

Gnomad OTH exome AF: 0.0290

GnomAD4 exome AF: 0.0199 AC: 28996 AN: 1453698 Hom.: 1686 Cov.: 36 AF XY: 0.0188 AC XY: 13616 AN XY: 723634

African (AFR) AF: 0.291 AC: 9741 AN: 33470

American (AMR) AF: 0.0224 AC: 1001 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.0193 AC: 505 AN: 26122

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39696

South Asian (SAS) AF: 0.00954 AC: 823 AN: 86244

European-Finnish (FIN) AF: 0.0189 AC: 861 AN: 45582

Middle Eastern (MID) AF: 0.0797 AC: 457 AN: 5734

European-Non Finnish (NFE) AF: 0.0125 AC: 13893 AN: 1111806

Other (OTH) AF: 0.0284 AC: 1714 AN: 60332

GnomAD4 genome AF: 0.0874 AC: 13294 AN: 152180 Hom.: 1599 Cov.: 33 AF XY: 0.0848 AC XY: 6309 AN XY: 74412

African (AFR) AF: 0.273 AC: 11332 AN: 41476

American (AMR) AF: 0.0396 AC: 605 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0211 AC: 73 AN: 3466

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5174

South Asian (SAS) AF: 0.00850 AC: 41 AN: 4826

European-Finnish (FIN) AF: 0.0184 AC: 195 AN: 10606

Middle Eastern (MID) AF: 0.0782 AC: 23 AN: 294

European-Non Finnish (NFE) AF: 0.0130 AC: 885 AN: 68018

Other (OTH) AF: 0.0582 AC: 123 AN: 2112

Alfa AF: 0.0546 Hom.: 166

Bravo AF: 0.0970

Asia WGS AF: 0.0190 AC: 69 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.89
DANN	Benign	0.52
PhyloP100		-0.78
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: rs56020676; hg19: chr22-36690120;