19-50255315-G-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001145809.2(MYH14):c.2041G>C(p.Gly681Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00483 in 1,550,188 control chromosomes in the GnomAD database, including 316 homozygotes. In-silico tool predicts a benign outcome for this variant. 10/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.026 ( 173 hom., cov: 32)

Exomes 𝑓: 0.0026 ( 143 hom. )

Consequence

MYH14
NM_001145809.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 2.06

Publications

2 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=0.002783388).

BP6

Variant 19-50255315-G-C is Benign according to our data. Variant chr19-50255315-G-C is described in ClinVar as Benign. ClinVar VariationId is 44054.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0861 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH14	NM_001145809.2 link	c.2041G>C	p.Gly681Arg	missense_variant	Exon 17 of 43	ENST00000642316.2	NP_001139281.1	Q7Z406-2A1L2Z2B3KWH4
MYH14	NM_001077186.2 link	c.1946-1984G>C		intron_variant	Intron 16 of 41		NP_001070654.1	Q7Z406-6B3KWH4
MYH14	NM_024729.4 link	c.1922-1984G>C		intron_variant	Intron 15 of 40		NP_079005.3	Q7Z406-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYH14	ENST00000642316.2 link	c.2041G>C	p.Gly681Arg	missense_variant	Exon 17 of 43		NM_001145809.2	ENSP00000493594.1		Q7Z406-2

Frequencies

GnomAD3 genomes

AF:

0.0257

AC:

3902

AN:

152086

Hom.:

175

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0886

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0103

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000415

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000500

Gnomad OTH

AF:

0.0191

GnomAD2 exomes

AF:

0.00555

AC:

852

AN:

153548

AF XY:

0.00427

show subpopulations

Gnomad AFR exome

AF:

0.0902

Gnomad AMR exome

AF:

0.00389

Gnomad ASJ exome

AF:

0.000235

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000402

Gnomad OTH exome

AF:

0.00161

GnomAD4 exome

AF:

0.00256

AC:

3578

AN:

1397984

Hom.:

143

Cov.:

AF XY:

0.00223

AC XY:

1540

AN XY:

689612

show subpopulations

African (AFR)

AF:

0.0908

AC:

2864

AN:

31546

American (AMR)

AF:

0.00482

AC:

172

AN:

35696

Ashkenazi Jewish (ASJ)

AF:

0.000238

AC:

AN:

25174

East Asian (EAS)

AF:

0.0000280

AC:

AN:

35720

South Asian (SAS)

AF:

0.000353

AC:

AN:

79216

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48576

Middle Eastern (MID)

AF:

0.00579

AC:

AN:

5696

European-Non Finnish (NFE)

AF:

0.000148

AC:

160

AN:

1078380

Other (OTH)

AF:

0.00542

AC:

314

AN:

57980

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

160

320

481

641

801

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

184

276

368

460

<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:

0.0257

AC:

3905

AN:

152204

Hom.:

173

Cov.:

AF XY:

0.0243

AC XY:

1807

AN XY:

74430

show subpopulations

African (AFR)

AF:

0.0885

AC:

3671

AN:

41490

American (AMR)

AF:

0.0103

AC:

157

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.000415

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000500

AC:

AN:

68022

Other (OTH)

AF:

0.0189

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

173

346

518

691

864

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

126

168

210

<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:

0.00238

Hom.:

Bravo

AF:

0.0290

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.00831

AC:

219

Asia WGS

AF:

0.00520

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Aug 10, 2018

GeneDx

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

- -

Nov 06, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:2

May 07, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Gly681Arg in Exon 17 of MYH14: This variant is not expected to have clinical sig nificance because it has been identified in 9.5% (67/702) of African American ch romosomes from a broad population by the NHLBI Exome Sequencing Project (http:// evs.gs.washington.edu/EVS; dbSNP rs75915336). -

Feb 25, 2021

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.37

CADD

Uncertain

(source)

DANN

Benign

0.95

Eigen

Benign

-0.50

Eigen_PC

Benign

-0.40

FATHMM_MKL

Uncertain

0.83

LIST_S2

Benign

0.55

.;T

MetaRNN

Benign

0.0028

T;T

MetaSVM

Benign

-1.0

PhyloP100

2.1

PrimateAI

Pathogenic

0.79

Sift4G

Uncertain

0.0060

.;D

Polyphen

0.0030

B;B

Vest4

0.21

MutPred

0.36

Gain of solvent accessibility (P = 0.0097);Gain of solvent accessibility (P = 0.0097);

MVP

0.082

MPC

1.2

ClinPred

0.0034

GERP RS

3.2

gMVP

0.49

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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