rs3842715

Variant names:

• chr22-36312004-CTCCTGTGA-C
• rs3842715
• NM_002473.6:c.1728+37_1728+44delTCACAGGA

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_002473.6(MYH9):​c.1728+37_1728+44delTCACAGGA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.229 in 1,611,926 control chromosomes in the GnomAD database, including 50,136 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.20 (3998 hom., cov: 26)
  • Exomes 𝑓: 0.23 (46138 hom.)
• Consequence: MYH9 NM_002473.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.178
• Publications: 7 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 -16 ACMG points.

• BP6: Variant 22-36312004-CTCCTGTGA-C is Benign according to our data. Variant chr22-36312004-CTCCTGTGA-C is described in ClinVar as Benign. ClinVar VariationId is 258730.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.607 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH9	NM_002473.6	c.1728+37_1728+44delTCACAGGA		intron_variant	Intron 14 of 40	ENST00000216181.11	NP_002464.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYH9	ENST00000216181.11	c.1728+37_1728+44delTCACAGGA		intron_variant	Intron 14 of 40	1	NM_002473.6	ENSP00000216181.6

Frequencies

GnomAD3 genomes AF: 0.200 AC: 30409 AN: 151968 Hom.: 3985 Cov.: 26

Gnomad AFR AF: 0.0820

Gnomad AMI AF: 0.182

Gnomad AMR AF: 0.256

Gnomad ASJ AF: 0.349

Gnomad EAS AF: 0.624

Gnomad SAS AF: 0.447

Gnomad FIN AF: 0.193

Gnomad MID AF: 0.263

Gnomad NFE AF: 0.202

Gnomad OTH AF: 0.230

GnomAD2 exomes AF: 0.272 AC: 68335 AN: 251072 AF XY: 0.280

Gnomad AFR exome AF: 0.0767

Gnomad AMR exome AF: 0.291

Gnomad ASJ exome AF: 0.351

Gnomad EAS exome AF: 0.621

Gnomad FIN exome AF: 0.196

Gnomad NFE exome AF: 0.203

Gnomad OTH exome AF: 0.252

GnomAD4 exome AF: 0.232 AC: 338216 AN: 1459838 Hom.: 46138 AF XY: 0.238 AC XY: 172938 AN XY: 726222

African (AFR) AF: 0.0764 AC: 2553 AN: 33418

American (AMR) AF: 0.286 AC: 12795 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.353 AC: 9219 AN: 26120

East Asian (EAS) AF: 0.623 AC: 24733 AN: 39682

South Asian (SAS) AF: 0.430 AC: 37073 AN: 86170

European-Finnish (FIN) AF: 0.195 AC: 10394 AN: 53254

Middle Eastern (MID) AF: 0.278 AC: 1398 AN: 5022

European-Non Finnish (NFE) AF: 0.202 AC: 224570 AN: 1111204

Other (OTH) AF: 0.257 AC: 15481 AN: 60256

GnomAD4 genome AF: 0.200 AC: 30445 AN: 152088 Hom.: 3998 Cov.: 26 AF XY: 0.208 AC XY: 15459 AN XY: 74326

African (AFR) AF: 0.0820 AC: 3403 AN: 41520

American (AMR) AF: 0.257 AC: 3927 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.349 AC: 1208 AN: 3462

East Asian (EAS) AF: 0.625 AC: 3221 AN: 5152

South Asian (SAS) AF: 0.446 AC: 2149 AN: 4814

European-Finnish (FIN) AF: 0.193 AC: 2037 AN: 10576

Middle Eastern (MID) AF: 0.269 AC: 79 AN: 294

European-Non Finnish (NFE) AF: 0.202 AC: 13759 AN: 67962

Other (OTH) AF: 0.235 AC: 497 AN: 2114

Alfa AF: 0.215 Hom.: 680

Bravo AF: 0.198

Asia WGS AF: 0.522 AC: 1814 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Jul 15, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 32% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 30. Only high quality variants are reported. -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal dominant nonsyndromic hearing loss 17 Benign:1

Sep 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Jun 16, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Macrothrombocytopenia and granulocyte inclusions with or without nephritis or sensorineural hearing loss Benign:1

Sep 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.18
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs3842715; hg19: chr22-36708049; COSMIC: COSV53381555;