rs6000233

Variant names:

• chr22-36291916-T-C
• rs6000233
• NM_002473.6:c.4344+70A>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.4344+70A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0316 in 1,609,530 control chromosomes in the GnomAD database, including 5,561 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (2798 hom., cov: 33)
  • Exomes 𝑓: 0.023 (2763 hom.)
• Consequence: MYH9 NM_002473.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -3.53
• Publications: 4 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=-0.93).
• BP6: Variant 22-36291916-T-C is Benign according to our data. Variant chr22-36291916-T-C is described in ClinVar as Benign. ClinVar VariationId is 1286826.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.357 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH9	NM_002473.6	c.4344+70A>G		intron_variant	Intron 31 of 40	ENST00000216181.11	NP_002464.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYH9	ENST00000216181.11	c.4344+70A>G		intron_variant	Intron 31 of 40	1	NM_002473.6	ENSP00000216181.6
MYH9	ENST00000685801.1	c.4407+70A>G		intron_variant	Intron 32 of 41			ENSP00000510688.1
MYH9	ENST00000691109.1	n.4639+70A>G		intron_variant	Intron 25 of 34

Frequencies

GnomAD3 genomes AF: 0.114 AC: 17296 AN: 152096 Hom.: 2784 Cov.: 33

Gnomad AFR AF: 0.362

Gnomad AMI AF: 0.0175

Gnomad AMR AF: 0.0563

Gnomad ASJ AF: 0.0210

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00931

Gnomad FIN AF: 0.0184

Gnomad MID AF: 0.0886

Gnomad NFE AF: 0.0136

Gnomad OTH AF: 0.0884

GnomAD4 exome AF: 0.0230 AC: 33530 AN: 1457316 Hom.: 2763 AF XY: 0.0215 AC XY: 15581 AN XY: 725104

African (AFR) AF: 0.379 AC: 12630 AN: 33368

American (AMR) AF: 0.0315 AC: 1408 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.0193 AC: 504 AN: 26122

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39688

South Asian (SAS) AF: 0.0105 AC: 901 AN: 85720

European-Finnish (FIN) AF: 0.0187 AC: 974 AN: 52152

Middle Eastern (MID) AF: 0.0855 AC: 410 AN: 4794

European-Non Finnish (NFE) AF: 0.0129 AC: 14331 AN: 1110578

Other (OTH) AF: 0.0393 AC: 2368 AN: 60196

GnomAD4 genome AF: 0.114 AC: 17356 AN: 152214 Hom.: 2798 Cov.: 33 AF XY: 0.111 AC XY: 8258 AN XY: 74414

African (AFR) AF: 0.362 AC: 15026 AN: 41488

American (AMR) AF: 0.0563 AC: 861 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0210 AC: 73 AN: 3470

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5164

South Asian (SAS) AF: 0.00911 AC: 44 AN: 4832

European-Finnish (FIN) AF: 0.0184 AC: 195 AN: 10622

Middle Eastern (MID) AF: 0.0986 AC: 29 AN: 294

European-Non Finnish (NFE) AF: 0.0136 AC: 926 AN: 68018

Other (OTH) AF: 0.0875 AC: 185 AN: 2114

Alfa AF: 0.0642 Hom.: 321

Bravo AF: 0.129

Asia WGS AF: 0.0330 AC: 115 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 29, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.029
DANN	Benign	0.30
PhyloP100		-3.5
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: rs6000233; hg19: chr22-36687962;