chr22-36300231-C-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 1P and 13B. PP2BP4_StrongBP6BS1BS2

The NM_002473.6(MYH9):c.2872G>A(p.Ala958Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000945 in 1,613,440 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00060 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00098 ( 3 hom. )

Consequence

MYH9
NM_002473.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:7

Conservation

PhyloP100: 6.13

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

PP2

Missense variant in the MYH9 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 43 curated pathogenic missense variants (we use a threshold of 10). The gene has 84 curated benign missense variants. Gene score misZ: 3.473 (above the threshold of 3.09). Trascript score misZ: 6.1231 (above the threshold of 3.09). GenCC associations: The gene is linked to May-Hegglin anomaly, autosomal dominant nonsyndromic hearing loss, macrothrombocytopenia and granulocyte inclusions with or without nephritis or sensorineural hearing loss, autosomal dominant nonsyndromic hearing loss 17.

BP4

Computational evidence support a benign effect (MetaRNN=0.04144463).

BP6

Variant 22-36300231-C-T is Benign according to our data. Variant chr22-36300231-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 164446.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=1, Likely_benign=5}.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000604 (92/152304) while in subpopulation NFE AF= 0.00116 (79/68028). AF 95% confidence interval is 0.000955. There are 0 homozygotes in gnomad4. There are 38 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 92 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH9	NM_002473.6 link	c.2872G>A	p.Ala958Thr	missense_variant	Exon 23 of 41	ENST00000216181.11	NP_002464.1	P35579-1A0A024R1N1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
MYH9	ENST00000216181.11 link	c.2872G>A	p.Ala958Thr	missense_variant	Exon 23 of 41	1	NM_002473.6	ENSP00000216181.6	P35579-1
MYH9	ENST00000685801.1 link	c.2935G>A	p.Ala979Thr	missense_variant	Exon 24 of 42			ENSP00000510688.1	A0A8I5KWT8
MYH9	ENST00000691109.1 link	n.3167G>A		non_coding_transcript_exon_variant	Exon 17 of 35

Frequencies

GnomAD3 genomes

AF:

0.000605

AC:

AN:

152188

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000217

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00116

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000738

AC:

185

AN:

250654

Hom.:

AF XY:

0.000708

AC XY:

AN XY:

135602

show subpopulations

Gnomad AFR exome

AF:

0.000369

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.000190

Gnomad NFE exome

AF:

0.00151

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000981

AC:

1433

AN:

1461136

Hom.:

Cov.:

AF XY:

0.000978

AC XY:

711

AN XY:

726900

show subpopulations

Gnomad4 AFR exome

AF:

0.000179

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000104

Gnomad4 FIN exome

AF:

0.000285

Gnomad4 NFE exome

AF:

0.00123

Gnomad4 OTH exome

AF:

0.000596

GnomAD4 genome

AF:

0.000604

AC:

AN:

152304

Hom.:

Cov.:

AF XY:

0.000510

AC XY:

AN XY:

74480

show subpopulations

Gnomad4 AFR

AF:

0.000217

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000188

Gnomad4 NFE

AF:

0.00116

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.00107

Hom.:

Bravo

AF:

0.000631

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00140

AC:

ExAC

AF:

0.000889

AC:

108

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00136

EpiControl

AF:

0.00124

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:7

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:3

Dec 07, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 24, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 29090586, 30349881, 29958610) -

Jan 05, 2017

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

MYH9: BS1 -

MYH9-related disorder

Benign:2

Dec 15, 2022

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Macrothrombocytopenia and granulocyte inclusions with or without nephritis or sensorineural hearing loss

Uncertain:1

ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: research

- -

Autosomal dominant nonsyndromic hearing loss 17

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

not specified

Benign:1

May 05, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Ala958Thr in exon 23 of MYH9: This variant is not expected to have clinical s ignificance because it has been identified in 0.2% (102/66426) of European chrom osomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org ; dbSNP rs151036570). In addition, this variant has been previously identified by our laboratory in two individuals with hearing loss that could be explained b y pathogenic variants in other genes, as well as in an unaffected parent. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Uncertain

-0.080

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.50

Eigen

Benign

-0.030

Eigen_PC

Benign

0.16

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.94

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.041

MetaSVM

Benign

-0.32

MutationAssessor

Benign

0.97

PrimateAI

Uncertain

0.66

PROVEAN

Uncertain

-2.4

REVEL

Uncertain

0.42

Sift

Benign

0.070

Sift4G

Benign

0.54

Polyphen

0.34

Vest4

0.36

MVP

0.79

MPC

0.49

ClinPred

0.036

GERP RS

5.3

RBP_binding_hub_radar

1.0

RBP_regulation_power_radar

2.1

Varity_R

0.30

gMVP

0.15

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over