NM_002473.6:c.2977-85G>A

Variant names:

• chr22-36299127-C-T
• rs2187776
• NM_002473.6:c.2977-85G>A

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.2977-85G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.96 in 1,584,540 control chromosomes in the GnomAD database, including 733,711 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.89 (61771 hom., cov: 31)
  • Exomes 𝑓: 0.97 (671940 hom.)
• Consequence: MYH9 NM_002473.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.74
• Publications: 12 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=-0.91).
• BP6: Variant 22-36299127-C-T is Benign according to our data. Variant chr22-36299127-C-T is described in ClinVar as Benign. ClinVar VariationId is 1225603.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.976 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.2977-85G>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.2977-85G>A		intron	N/A	ENSP00000216181.6
	MYH9	ENST00000685801.1		c.3040-85G>A		intron	N/A	ENSP00000510688.1
	MYH9	ENST00000691109.1		n.3272-85G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.893 AC: 135713 AN: 152016 Hom.: 61739 Cov.: 31

Gnomad AFR AF: 0.691

Gnomad AMI AF: 0.995

Gnomad AMR AF: 0.951

Gnomad ASJ AF: 0.958

Gnomad EAS AF: 0.999

Gnomad SAS AF: 0.984

Gnomad FIN AF: 0.963

Gnomad MID AF: 0.918

Gnomad NFE AF: 0.971

Gnomad OTH AF: 0.913

GnomAD4 exome AF: 0.967 AC: 1385852 AN: 1432406 Hom.: 671940 AF XY: 0.969 AC XY: 691897 AN XY: 714286

African (AFR) AF: 0.681 AC: 22314 AN: 32780

American (AMR) AF: 0.970 AC: 43300 AN: 44620

Ashkenazi Jewish (ASJ) AF: 0.961 AC: 24911 AN: 25930

East Asian (EAS) AF: 1.00 AC: 39410 AN: 39424

South Asian (SAS) AF: 0.985 AC: 83849 AN: 85164

European-Finnish (FIN) AF: 0.964 AC: 47030 AN: 48800

Middle Eastern (MID) AF: 0.929 AC: 5098 AN: 5486

European-Non Finnish (NFE) AF: 0.975 AC: 1063098 AN: 1090742

Other (OTH) AF: 0.956 AC: 56842 AN: 59460

GnomAD4 genome AF: 0.893 AC: 135793 AN: 152134 Hom.: 61771 Cov.: 31 AF XY: 0.895 AC XY: 66574 AN XY: 74388

African (AFR) AF: 0.690 AC: 28595 AN: 41418

American (AMR) AF: 0.951 AC: 14559 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.958 AC: 3325 AN: 3470

East Asian (EAS) AF: 0.999 AC: 5164 AN: 5168

South Asian (SAS) AF: 0.984 AC: 4746 AN: 4822

European-Finnish (FIN) AF: 0.963 AC: 10219 AN: 10614

Middle Eastern (MID) AF: 0.922 AC: 271 AN: 294

European-Non Finnish (NFE) AF: 0.971 AC: 66074 AN: 68018

Other (OTH) AF: 0.914 AC: 1933 AN: 2114

Alfa AF: 0.945 Hom.: 86745

Bravo AF: 0.882

Asia WGS AF: 0.970 AC: 3375 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

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 22, 2018

GeneDx

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	-0.91
CADD	Benign	0.013
DANN	Benign	0.59
PhyloP100		-2.7
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: rs2187776; hg19: chr22-36695173;