rs3752463

Variant names:

• chr22-36320164-G-A
• rs3752463
• NM_002473.6:c.1012+56C>T

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.1012+56C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.55 in 1,611,550 control chromosomes in the GnomAD database, including 253,933 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.48 (19090 hom., cov: 32)
  • Exomes 𝑓: 0.56 (234843 hom.)
• Consequence: MYH9 NM_002473.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -2.49
• Publications: 8 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=-0.91).
• BP6: Variant 22-36320164-G-A is Benign according to our data. Variant chr22-36320164-G-A is described in ClinVar as Benign. ClinVar VariationId is 1289525.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.589 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH9	NM_002473.6	c.1012+56C>T		intron_variant	Intron 9 of 40	ENST00000216181.11	NP_002464.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYH9	ENST00000216181.11	c.1012+56C>T		intron_variant	Intron 9 of 40	1	NM_002473.6	ENSP00000216181.6

Frequencies

GnomAD3 genomes AF: 0.476 AC: 72096 AN: 151522 Hom.: 19090 Cov.: 32

Gnomad AFR AF: 0.265

Gnomad AMI AF: 0.681

Gnomad AMR AF: 0.576

Gnomad ASJ AF: 0.469

Gnomad EAS AF: 0.154

Gnomad SAS AF: 0.363

Gnomad FIN AF: 0.589

Gnomad MID AF: 0.570

Gnomad NFE AF: 0.594

Gnomad OTH AF: 0.497

GnomAD4 exome AF: 0.558 AC: 814043 AN: 1459910 Hom.: 234843 AF XY: 0.553 AC XY: 401770 AN XY: 726348

African (AFR) AF: 0.256 AC: 8554 AN: 33460

American (AMR) AF: 0.604 AC: 26980 AN: 44660

Ashkenazi Jewish (ASJ) AF: 0.453 AC: 11827 AN: 26120

East Asian (EAS) AF: 0.144 AC: 5717 AN: 39684

South Asian (SAS) AF: 0.400 AC: 34472 AN: 86200

European-Finnish (FIN) AF: 0.598 AC: 31238 AN: 52254

Middle Eastern (MID) AF: 0.556 AC: 3205 AN: 5764

European-Non Finnish (NFE) AF: 0.594 AC: 660460 AN: 1111410

Other (OTH) AF: 0.523 AC: 31590 AN: 60358

GnomAD4 genome AF: 0.476 AC: 72105 AN: 151640 Hom.: 19090 Cov.: 32 AF XY: 0.473 AC XY: 35043 AN XY: 74060

African (AFR) AF: 0.265 AC: 10956 AN: 41386

American (AMR) AF: 0.575 AC: 8773 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.469 AC: 1623 AN: 3464

East Asian (EAS) AF: 0.153 AC: 793 AN: 5170

South Asian (SAS) AF: 0.364 AC: 1750 AN: 4810

European-Finnish (FIN) AF: 0.589 AC: 6168 AN: 10480

Middle Eastern (MID) AF: 0.568 AC: 166 AN: 292

European-Non Finnish (NFE) AF: 0.594 AC: 40226 AN: 67772

Other (OTH) AF: 0.492 AC: 1040 AN: 2112

Alfa AF: 0.537 Hom.: 2971

Bravo AF: 0.466

Asia WGS AF: 0.242 AC: 846 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 24, 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 86% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 80. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.15
DANN	Benign	0.41
PhyloP100		-2.5
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: rs3752463; hg19: chr22-36716209; COSMIC: COSV53383262; COSMIC: COSV53383262;