chr22-36305891-G-T

Variant names:

• chr22-36305891-G-T
• rs76330062
• NM_002473.6:c.2159+39C>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_002473.6(MYH9):​c.2159+39C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0424 in 1,611,282 control chromosomes in the GnomAD database, including 1,682 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.033 (117 hom., cov: 33)
  • Exomes 𝑓: 0.043 (1565 hom.)
• Consequence: MYH9 NM_002473.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.65
• Publications: 3 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 22-36305891-G-T is Benign according to our data. Variant chr22-36305891-G-T is described in ClinVar as Benign. ClinVar VariationId is 258733.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0328 (5002/152296) while in subpopulation NFE AF = 0.0493 (3356/68008). AF 95% confidence interval is 0.048. There are 117 homozygotes in GnomAd4. There are 2344 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 5002 AD gene.

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.2159+39C>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.2159+39C>A		intron	N/A	ENSP00000216181.6
	MYH9	ENST00000687922.1		n.534C>A		non_coding_transcript_exon	Exon 3 of 3
	MYH9	ENST00000685801.1		c.2222+39C>A		intron	N/A	ENSP00000510688.1

Frequencies

GnomAD3 genomes AF: 0.0329 AC: 5000 AN: 152178 Hom.: 117 Cov.: 33

Gnomad AFR AF: 0.0102

Gnomad AMI AF: 0.0637

Gnomad AMR AF: 0.0405

Gnomad ASJ AF: 0.0530

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00746

Gnomad FIN AF: 0.0228

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.0493

Gnomad OTH AF: 0.0339

GnomAD2 exomes AF: 0.0345 AC: 8589 AN: 249288 AF XY: 0.0350

Gnomad AFR exome AF: 0.00938

Gnomad AMR exome AF: 0.0289

Gnomad ASJ exome AF: 0.0582

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0231

Gnomad NFE exome AF: 0.0517

Gnomad OTH exome AF: 0.0454

GnomAD4 exome AF: 0.0434 AC: 63309 AN: 1458986 Hom.: 1565 Cov.: 32 AF XY: 0.0426 AC XY: 30908 AN XY: 725762

African (AFR) AF: 0.00760 AC: 254 AN: 33424

American (AMR) AF: 0.0300 AC: 1342 AN: 44668

Ashkenazi Jewish (ASJ) AF: 0.0583 AC: 1520 AN: 26092

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39656

South Asian (SAS) AF: 0.00886 AC: 764 AN: 86234

European-Finnish (FIN) AF: 0.0244 AC: 1266 AN: 51872

Middle Eastern (MID) AF: 0.0416 AC: 234 AN: 5620

European-Non Finnish (NFE) AF: 0.0498 AC: 55365 AN: 1111162

Other (OTH) AF: 0.0425 AC: 2559 AN: 60258

GnomAD4 genome AF: 0.0328 AC: 5002 AN: 152296 Hom.: 117 Cov.: 33 AF XY: 0.0315 AC XY: 2344 AN XY: 74482

African (AFR) AF: 0.0101 AC: 422 AN: 41578

American (AMR) AF: 0.0405 AC: 620 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0530 AC: 184 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00767 AC: 37 AN: 4824

European-Finnish (FIN) AF: 0.0228 AC: 242 AN: 10622

Middle Eastern (MID) AF: 0.0408 AC: 12 AN: 294

European-Non Finnish (NFE) AF: 0.0493 AC: 3356 AN: 68008

Other (OTH) AF: 0.0336 AC: 71 AN: 2116

Alfa AF: 0.0202 Hom.: 13

Bravo AF: 0.0347

Asia WGS AF: 0.00462 AC: 17 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Jun 29, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	3.4
DANN	Benign	0.74
PhyloP100		1.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs76330062; hg19: chr22-36701937;