rs5756142

Variant names:

• chr22-36314011-A-G
• rs5756142
• NM_002473.6:c.1554+134T>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.1554+134T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.608 in 1,187,618 control chromosomes in the GnomAD database, including 232,022 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.53 (23666 hom., cov: 31)
  • Exomes 𝑓: 0.62 (208356 hom.)
• Consequence: MYH9 NM_002473.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.57
• Publications: 6 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 22-36314011-A-G is Benign according to our data. Variant chr22-36314011-A-G is described in ClinVar as [Benign]. Clinvar id is 1227147.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.67 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH9	NM_002473.6	c.1554+134T>C		intron_variant	Intron 13 of 40	ENST00000216181.11	NP_002464.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYH9	ENST00000216181.11	c.1554+134T>C		intron_variant	Intron 13 of 40	1	NM_002473.6	ENSP00000216181.6

Frequencies

GnomAD3 genomes AF: 0.527 AC: 79910 AN: 151692 Hom.: 23672 Cov.: 31

Gnomad AFR AF: 0.268

Gnomad AMI AF: 0.760

Gnomad AMR AF: 0.611

Gnomad ASJ AF: 0.527

Gnomad EAS AF: 0.221

Gnomad SAS AF: 0.383

Gnomad FIN AF: 0.651

Gnomad MID AF: 0.516

Gnomad NFE AF: 0.675

Gnomad OTH AF: 0.550

GnomAD4 exome AF: 0.620 AC: 642611 AN: 1035810 Hom.: 208356 AF XY: 0.614 AC XY: 322103 AN XY: 524694

African (AFR) AF: 0.249 AC: 6153 AN: 24748

American (AMR) AF: 0.632 AC: 22410 AN: 35438

Ashkenazi Jewish (ASJ) AF: 0.529 AC: 12073 AN: 22810

East Asian (EAS) AF: 0.217 AC: 7482 AN: 34482

South Asian (SAS) AF: 0.414 AC: 30012 AN: 72558

European-Finnish (FIN) AF: 0.653 AC: 29936 AN: 45834

Middle Eastern (MID) AF: 0.509 AC: 2378 AN: 4676

European-Non Finnish (NFE) AF: 0.675 AC: 505502 AN: 749158

Other (OTH) AF: 0.578 AC: 26665 AN: 46106

GnomAD4 genome AF: 0.526 AC: 79909 AN: 151808 Hom.: 23666 Cov.: 31 AF XY: 0.522 AC XY: 38708 AN XY: 74176

African (AFR) AF: 0.268 AC: 11092 AN: 41406

American (AMR) AF: 0.610 AC: 9317 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.527 AC: 1827 AN: 3464

East Asian (EAS) AF: 0.220 AC: 1136 AN: 5154

South Asian (SAS) AF: 0.385 AC: 1850 AN: 4810

European-Finnish (FIN) AF: 0.651 AC: 6857 AN: 10534

Middle Eastern (MID) AF: 0.521 AC: 152 AN: 292

European-Non Finnish (NFE) AF: 0.675 AC: 45836 AN: 67862

Other (OTH) AF: 0.545 AC: 1150 AN: 2112

Alfa AF: 0.612 Hom.: 6087

Bravo AF: 0.515

Asia WGS AF: 0.255 AC: 887 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	-0.90
CADD	Benign	0.45
DANN	Benign	0.37
PhyloP100		-1.6
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: rs5756142; hg19: chr22-36710056;