chr19-50276825-C-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001145809.2(MYH14):c.3749C>A(p.Ala1250Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0268 in 1,599,232 control chromosomes in the GnomAD database, including 651 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1250V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.019 ( 40 hom., cov: 31)

Exomes 𝑓: 0.028 ( 611 hom. )

Consequence

MYH14
NM_001145809.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 0.552

Publications

14 publications found

Variant links:

Genes affected

MYH14 (HGNC:23212): (myosin heavy chain 14) This gene encodes a member of the myosin superfamily. The protein represents a conventional non-muscle myosin; it should not be confused with the unconventional myosin-14 (MYO14). Myosins are actin-dependent motor proteins with diverse functions including regulation of cytokinesis, cell motility, and cell polarity. Mutations in this gene result in one form of autosomal dominant hearing impairment. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2011]

MYH14 Gene-Disease associations (from GenCC):

autosomal dominant nonsyndromic hearing loss 4A
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Ambry Genetics
peripheral neuropathy-myopathy-hoarseness-hearing loss syndrome
Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)
nonsyndromic genetic hearing loss
Inheritance: AD Classification: MODERATE Submitted by: ClinGen
autosomal dominant nonsyndromic hearing loss
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

MYH14 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.005027652).

BP6

Variant 19-50276825-C-A is Benign according to our data. Variant chr19-50276825-C-A is described in ClinVar as Benign. ClinVar VariationId is 44068.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0192 (2888/150728) while in subpopulation NFE AF = 0.0294 (1993/67724). AF 95% confidence interval is 0.0284. There are 40 homozygotes in GnomAd4. There are 1383 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High AC in GnomAd4 at 2888 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH14	NM_001145809.2 link	c.3749C>A	p.Ala1250Glu	missense_variant	Exon 29 of 43	ENST00000642316.2	NP_001139281.1	Q7Z406-2A1L2Z2B3KWH4
MYH14	NM_001077186.2 link	c.3650C>A	p.Ala1217Glu	missense_variant	Exon 28 of 42		NP_001070654.1	Q7Z406-6B3KWH4
MYH14	NM_024729.4 link	c.3626C>A	p.Ala1209Glu	missense_variant	Exon 27 of 41		NP_079005.3	Q7Z406-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYH14	ENST00000642316.2 link	c.3749C>A	p.Ala1250Glu	missense_variant	Exon 29 of 43		NM_001145809.2	ENSP00000493594.1		Q7Z406-2

Frequencies

GnomAD3 genomes

AF:

0.0192

AC:

2887

AN:

150608

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00596

Gnomad AMI

AF:

0.0100

Gnomad AMR

AF:

0.0218

Gnomad ASJ

AF:

0.00666

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00474

Gnomad FIN

AF:

0.0208

Gnomad MID

AF:

0.0159

Gnomad NFE

AF:

0.0294

Gnomad OTH

AF:

0.0226

GnomAD2 exomes

AF:

0.0192

AC:

4754

AN:

248174

AF XY:

0.0196

show subpopulations

Gnomad AFR exome

AF:

0.00516

Gnomad AMR exome

AF:

0.0151

Gnomad ASJ exome

AF:

0.00727

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0204

Gnomad NFE exome

AF:

0.0299

Gnomad OTH exome

AF:

0.0232

GnomAD4 exome

AF:

0.0276

AC:

39916

AN:

1448504

Hom.:

611

Cov.:

AF XY:

0.0270

AC XY:

19449

AN XY:

720538

show subpopulations

African (AFR)

AF:

0.00466

AC:

154

AN:

33052

American (AMR)

AF:

0.0166

AC:

734

AN:

44232

Ashkenazi Jewish (ASJ)

AF:

0.00669

AC:

171

AN:

25578

East Asian (EAS)

AF:

0.0000782

AC:

AN:

38360

South Asian (SAS)

AF:

0.00502

AC:

432

AN:

86076

European-Finnish (FIN)

AF:

0.0227

AC:

1193

AN:

52440

Middle Eastern (MID)

AF:

0.0161

AC:

AN:

5026

European-Non Finnish (NFE)

AF:

0.0323

AC:

35685

AN:

1104374

Other (OTH)

AF:

0.0246

AC:

1463

AN:

59366

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

2090

4179

6269

8358

10448

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1358

2716

4074

5432

6790

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0192

AC:

2888

AN:

150728

Hom.:

Cov.:

AF XY:

0.0188

AC XY:

1383

AN XY:

73682

show subpopulations

African (AFR)

AF:

0.00595

AC:

245

AN:

41200

American (AMR)

AF:

0.0217

AC:

329

AN:

15128

Ashkenazi Jewish (ASJ)

AF:

0.00666

AC:

AN:

3454

East Asian (EAS)

AF:

0.00

AC:

AN:

4978

South Asian (SAS)

AF:

0.00475

AC:

AN:

4636

European-Finnish (FIN)

AF:

0.0208

AC:

215

AN:

10316

Middle Eastern (MID)

AF:

0.0171

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0294

AC:

1993

AN:

67724

Other (OTH)

AF:

0.0224

AC:

AN:

2100

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.511

Heterozygous variant carriers

147

294

440

587

734

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

102

136

170

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0259

Hom.:

181

Bravo

AF:

0.0191

TwinsUK

AF:

0.0286

AC:

106

ALSPAC

AF:

0.0317

AC:

122

ESP6500AA

AF:

0.00748

AC:

ESP6500EA

AF:

0.0292

AC:

249

ExAC

AF:

0.0193

AC:

2338

Asia WGS

AF:

0.00260

AC:

AN:

3478

EpiCase

AF:

0.0295

EpiControl

AF:

0.0296

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Dec 06, 2017

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. -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Apr 12, 2016

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

May 07, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Ala1250Glu in Exon 29 of MYH14: This variant is not expected to have clinical si gnificance because it has been identified in 3.0% (209/6938) of European America n chromosomes from a broad population by the NHLBI Exome Sequencing Project (htt p://evs.gs.washington.edu/EVS; dbSNP rs11669191). -

not provided

Benign:4

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Dec 07, 2018

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 29, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Autosomal dominant nonsyndromic hearing loss 4A

Benign:1

Jan 12, 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.50

CADD

Benign

(source)

DANN

Benign

0.95

DEOGEN2

Uncertain

0.51

.;.;D;.;.;D;T

Eigen

Benign

-0.43

Eigen_PC

Benign

-0.53

FATHMM_MKL

Benign

0.30

LIST_S2

Benign

0.82

.;T;T;.;T;.;D

MetaRNN

Benign

0.0050

T;T;T;T;T;T;T

MetaSVM

Benign

-0.43

MutationAssessor

Benign

1.3

.;.;L;.;.;L;.

PhyloP100

0.55

PrimateAI

Benign

0.45

PROVEAN

Uncertain

-2.5

.;N;.;.;.;.;.

REVEL

Uncertain

0.42

Sift

Benign

0.18

.;T;.;.;.;.;.

Sift4G

Benign

0.21

T;T;T;.;T;T;T

Polyphen

0.65

P;P;P;P;P;P;.

Vest4

0.082

MPC

0.22

ClinPred

0.037

GERP RS

0.032

Varity_R

0.11

gMVP

0.35

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over