rs55994070

Variant names:

• chr22-36281982-G-A
• rs55994070
• NM_002473.6:c.*686C>T

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.*686C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00711 in 233,722 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0074 (9 hom., cov: 33)
  • Exomes 𝑓: 0.0066 (1 hom.)
• Consequence: MYH9 NM_002473.6 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.126
• 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: Labcorp Genetics (formerly Invitae), Orphanet, G2P, 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=-0.73).
• BP6: Variant 22-36281982-G-A is Benign according to our data. Variant chr22-36281982-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 341472.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 = 0.00739 (1126/152404) while in subpopulation NFE AF = 0.00985 (670/68038). AF 95% confidence interval is 0.00923. There are 9 homozygotes in GnomAd4. There are 625 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1126 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH9	NM_002473.6	MANE Select	c.*686C>T		3_prime_UTR	Exon 41 of 41	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.*686C>T		3_prime_UTR	Exon 41 of 41	ENSP00000216181.6	P35579-1
	MYH9	ENST00000685801.1		c.*686C>T		3_prime_UTR	Exon 42 of 42	ENSP00000510688.1	A0A8I5KWT8
	MYH9	ENST00000955568.1		c.*686C>T		3_prime_UTR	Exon 42 of 42	ENSP00000625627.1

Frequencies

GnomAD3 genomes AF: 0.00740 AC: 1127 AN: 152286 Hom.: 9 Cov.: 33

Gnomad AFR AF: 0.000964

Gnomad AMI AF: 0.0143

Gnomad AMR AF: 0.00248

Gnomad ASJ AF: 0.0210

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.0260

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00985

Gnomad OTH AF: 0.00669

GnomAD4 exome AF: 0.00658 AC: 535 AN: 81318 Hom.: 1 Cov.: 0 AF XY: 0.00648 AC XY: 243 AN XY: 37524

African (AFR) AF: 0.000261 AC: 1 AN: 3830

American (AMR) AF: 0.00271 AC: 7 AN: 2584

Ashkenazi Jewish (ASJ) AF: 0.0201 AC: 102 AN: 5066

East Asian (EAS) AF: 0.00 AC: 0 AN: 11320

South Asian (SAS) AF: 0.00 AC: 0 AN: 706

European-Finnish (FIN) AF: 0.0286 AC: 14 AN: 490

Middle Eastern (MID) AF: 0.00617 AC: 3 AN: 486

European-Non Finnish (NFE) AF: 0.00738 AC: 370 AN: 50120

Other (OTH) AF: 0.00566 AC: 38 AN: 6716

GnomAD4 genome AF: 0.00739 AC: 1126 AN: 152404 Hom.: 9 Cov.: 33 AF XY: 0.00839 AC XY: 625 AN XY: 74530

African (AFR) AF: 0.000961 AC: 40 AN: 41606

American (AMR) AF: 0.00248 AC: 38 AN: 15314

Ashkenazi Jewish (ASJ) AF: 0.0210 AC: 73 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4830

European-Finnish (FIN) AF: 0.0260 AC: 276 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00985 AC: 670 AN: 68038

Other (OTH) AF: 0.00662 AC: 14 AN: 2116

Alfa AF: 0.0113 Hom.: 2

Bravo AF: 0.00505

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Autosomal dominant nonsyndromic hearing loss 17 (1)
-	-	1	MYH9-related disorder (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	10
DANN	Benign	0.83
PhyloP100		0.13
Mutation Taster		=100/0	polymorphism

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: rs55994070; hg19: chr22-36678028;