rs1557529

Variant names:

• chr22-36309484-A-G
• rs1557529
• NM_002473.6:c.1729-88T>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.1729-88T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.951 in 961,442 control chromosomes in the GnomAD database, including 438,242 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.88 (60517 hom., cov: 33)
  • Exomes 𝑓: 0.96 (377725 hom.)
• Consequence: MYH9 NM_002473.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.0880
• Publications: 13 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=-0.9).
• BP6: Variant 22-36309484-A-G is Benign according to our data. Variant chr22-36309484-A-G is described in ClinVar as Benign. ClinVar VariationId is 1286206.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.977 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH9	NM_002473.6	c.1729-88T>C		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.1729-88T>C		intron_variant	Intron 14 of 40	1	NM_002473.6	ENSP00000216181.6

Frequencies

GnomAD3 genomes AF: 0.879 AC: 133769 AN: 152134 Hom.: 60471 Cov.: 33

Gnomad AFR AF: 0.640

Gnomad AMI AF: 0.995

Gnomad AMR AF: 0.954

Gnomad ASJ AF: 0.958

Gnomad EAS AF: 0.999

Gnomad SAS AF: 0.984

Gnomad FIN AF: 0.963

Gnomad MID AF: 0.927

Gnomad NFE AF: 0.971

Gnomad OTH AF: 0.911

GnomAD4 exome AF: 0.965 AC: 780513 AN: 809190 Hom.: 377725 AF XY: 0.967 AC XY: 411006 AN XY: 425180

African (AFR) AF: 0.633 AC: 13330 AN: 21044

American (AMR) AF: 0.972 AC: 38778 AN: 39900

Ashkenazi Jewish (ASJ) AF: 0.962 AC: 20980 AN: 21816

East Asian (EAS) AF: 1.00 AC: 36231 AN: 36242

South Asian (SAS) AF: 0.985 AC: 70512 AN: 71582

European-Finnish (FIN) AF: 0.963 AC: 49367 AN: 51268

Middle Eastern (MID) AF: 0.932 AC: 4226 AN: 4536

European-Non Finnish (NFE) AF: 0.973 AC: 509798 AN: 523762

Other (OTH) AF: 0.955 AC: 37291 AN: 39040

GnomAD4 genome AF: 0.879 AC: 133867 AN: 152252 Hom.: 60517 Cov.: 33 AF XY: 0.882 AC XY: 65684 AN XY: 74464

African (AFR) AF: 0.641 AC: 26598 AN: 41506

American (AMR) AF: 0.954 AC: 14598 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.958 AC: 3323 AN: 3468

East Asian (EAS) AF: 0.999 AC: 5180 AN: 5184

South Asian (SAS) AF: 0.985 AC: 4755 AN: 4828

European-Finnish (FIN) AF: 0.963 AC: 10220 AN: 10612

Middle Eastern (MID) AF: 0.935 AC: 275 AN: 294

European-Non Finnish (NFE) AF: 0.971 AC: 66082 AN: 68030

Other (OTH) AF: 0.912 AC: 1929 AN: 2116

Alfa AF: 0.816 Hom.: 13288

Bravo AF: 0.869

Asia WGS AF: 0.970 AC: 3373 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

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

- -

not specified Benign:1

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 80% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 74. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	2.2
DANN	Benign	0.37
PhyloP100		-0.088
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1557529; hg19: chr22-36705529;