19-50301835-G-A

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_001145809.2(MYH14):c.5644G>A(p.Ala1882Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000682 in 1,613,542 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

MYH14
NM_001145809.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.95

Publications

3 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: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.157805).

BS2

High AC in GnomAdExome4 at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH14	NM_001145809.2 link	c.5644G>A	p.Ala1882Thr	missense_variant	Exon 40 of 43	ENST00000642316.2	NP_001139281.1	Q7Z406-2A1L2Z2B3KWH4
MYH14	NM_001077186.2 link	c.5545G>A	p.Ala1849Thr	missense_variant	Exon 39 of 42		NP_001070654.1	Q7Z406-6B3KWH4
MYH14	NM_024729.4 link	c.5521G>A	p.Ala1841Thr	missense_variant	Exon 38 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.5644G>A	p.Ala1882Thr	missense_variant	Exon 40 of 43		NM_001145809.2	ENSP00000493594.1		Q7Z406-2

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000162

AC:

AN:

247504

AF XY:

0.0000223

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000291

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000547

AC:

AN:

1461214

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

726866

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33474

American (AMR)

AF:

0.0000672

AC:

AN:

44618

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26098

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.0000464

AC:

AN:

86176

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53314

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

9.00e-7

AC:

AN:

1111706

Other (OTH)

AF:

0.00

AC:

AN:

60364

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.0000197

AC:

AN:

152328

Hom.:

Cov.:

AF XY:

0.0000268

AC XY:

AN XY:

74488

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41574

American (AMR)

AF:

0.0000654

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.000207

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68036

Other (OTH)

AF:

0.00

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.0000248

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jul 20, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.Ala1882Thr variant in MYH14 has not been previously reported in individual s with hearing loss, but has been identified in 3/30662 South Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; db SNP rs200566974). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. Computational p rediction tools and conservation analysis do not provide strong support for or a gainst an impact to the protein. In summary, the clinical significance of the p. Ala1882Thr variant is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.078

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.34

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.28

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

Eigen

Benign

0.053

Eigen_PC

Benign

-0.031

FATHMM_MKL

Benign

0.52

LIST_S2

Uncertain

0.91

.;D;D;D;.;D;.

M_CAP

Benign

0.043

MetaRNN

Benign

0.16

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

MetaSVM

Uncertain

-0.27

MutationAssessor

Benign

1.6

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

PhyloP100

2.0

PrimateAI

Uncertain

0.51

PROVEAN

Uncertain

-2.4

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

REVEL

Uncertain

0.34

Sift

Benign

0.17

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

Sift4G

Benign

0.57

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

Polyphen

0.94

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

Vest4

0.18

MVP

0.70

MPC

0.21

ClinPred

0.50

GERP RS

1.9

Varity_R

0.062

gMVP

0.081

Mutation Taster

=85/15

polymorphism

(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