rs41279999

Variant names:

• chr22-36298908-C-G
• rs41279999
• NM_002473.6:c.3100+11G>C

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.3100+11G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0323 in 1,613,458 control chromosomes in the GnomAD database, including 1,177 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.031 (119 hom., cov: 32)
  • Exomes 𝑓: 0.032 (1058 hom.)
• Consequence: MYH9 NM_002473.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -1.31
• Publications: 5 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 22-36298908-C-G is Benign according to our data. Variant chr22-36298908-C-G is described in ClinVar as Benign. ClinVar VariationId is 44556.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0903 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.3100+11G>C		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.3100+11G>C		intron	N/A	ENSP00000216181.6	P35579-1
	MYH9	ENST00000685801.1		c.3163+11G>C		intron	N/A	ENSP00000510688.1	A0A8I5KWT8
	MYH9	ENST00000955568.1		c.3163+11G>C		intron	N/A	ENSP00000625627.1

Frequencies

GnomAD3 genomes AF: 0.0308 AC: 4694 AN: 152162 Hom.: 118 Cov.: 32

Gnomad AFR AF: 0.0222

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.0220

Gnomad ASJ AF: 0.0138

Gnomad EAS AF: 0.0981

Gnomad SAS AF: 0.0753

Gnomad FIN AF: 0.0568

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0270

Gnomad OTH AF: 0.0315

GnomAD2 exomes AF: 0.0381 AC: 9567 AN: 251260 AF XY: 0.0400

Gnomad AFR exome AF: 0.0206

Gnomad AMR exome AF: 0.0158

Gnomad ASJ exome AF: 0.0178

Gnomad EAS exome AF: 0.0919

Gnomad FIN exome AF: 0.0490

Gnomad NFE exome AF: 0.0285

Gnomad OTH exome AF: 0.0326

GnomAD4 exome AF: 0.0325 AC: 47433 AN: 1461178 Hom.: 1058 Cov.: 32 AF XY: 0.0335 AC XY: 24362 AN XY: 726924

African (AFR) AF: 0.0211 AC: 707 AN: 33466

American (AMR) AF: 0.0158 AC: 707 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.0163 AC: 425 AN: 26128

East Asian (EAS) AF: 0.105 AC: 4178 AN: 39686

South Asian (SAS) AF: 0.0703 AC: 6059 AN: 86222

European-Finnish (FIN) AF: 0.0501 AC: 2658 AN: 53106

Middle Eastern (MID) AF: 0.0228 AC: 128 AN: 5610

European-Non Finnish (NFE) AF: 0.0274 AC: 30515 AN: 1111868

Other (OTH) AF: 0.0341 AC: 2056 AN: 60380

GnomAD4 genome AF: 0.0309 AC: 4702 AN: 152280 Hom.: 119 Cov.: 32 AF XY: 0.0324 AC XY: 2416 AN XY: 74464

African (AFR) AF: 0.0224 AC: 932 AN: 41552

American (AMR) AF: 0.0221 AC: 339 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0138 AC: 48 AN: 3468

East Asian (EAS) AF: 0.0973 AC: 505 AN: 5188

South Asian (SAS) AF: 0.0760 AC: 366 AN: 4818

European-Finnish (FIN) AF: 0.0568 AC: 603 AN: 10618

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0270 AC: 1835 AN: 68010

Other (OTH) AF: 0.0307 AC: 65 AN: 2114

Alfa AF: 0.0267 Hom.: 16

Bravo AF: 0.0280

Asia WGS AF: 0.0860 AC: 299 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	4	not specified (4)
-	-	1	Autosomal dominant nonsyndromic hearing loss 17 (1)
-	-	1	MYH9-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.84
DANN	Benign	0.56
PhyloP100		-1.3
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: rs41279999; hg19: chr22-36694954; COSMIC: COSV53385112; COSMIC: COSV53385112;