dbSNP rs771755654: MYH14:p.Glu1433Lys (chr19-50281600-G-A) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 1P and 6B. PP5BP4BS1_SupportingBS2

The NM_001145809.2(MYH14):c.4297G>A(p.Glu1433Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000359 in 1,586,656 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000033 ( 0 hom. )

Consequence

MYH14
NM_001145809.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:2

Conservation

PhyloP100: 7.61

Publications

0 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 -5 ACMG points.

PP5

Variant 19-50281600-G-A is Pathogenic according to our data. Variant chr19-50281600-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 228877.

BP4

Computational evidence support a benign effect (MetaRNN=0.3606447). . Strength limited to SUPPORTING due to the PP5.

BS1

Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.0000328 (47/1434450) while in subpopulation MID AF = 0.000238 (1/4204). AF 95% confidence interval is 0.000074. There are 0 homozygotes in GnomAdExome4. There are 25 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High AC in GnomAd4 at 10 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001145809.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
MYH14	NM_001145809.2	MANE Select	c.4297G>A	p.Glu1433Lys	missense	Exon 33 of 43	NP_001139281.1
MYH14	NM_001077186.2		c.4198G>A	p.Glu1400Lys	missense	Exon 32 of 42	NP_001070654.1
MYH14	NM_024729.4		c.4174G>A	p.Glu1392Lys	missense	Exon 31 of 41	NP_079005.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
MYH14	ENST00000642316.2	MANE Select	c.4297G>A	p.Glu1433Lys	missense	Exon 33 of 43	ENSP00000493594.1
MYH14	ENST00000425460.6	TSL:5	c.4198G>A	p.Glu1400Lys	missense	Exon 32 of 42	ENSP00000407879.1
MYH14	ENST00000598205.5	TSL:5	c.4198G>A	p.Glu1400Lys	missense	Exon 32 of 42	ENSP00000472543.1

Frequencies

GnomAD3 genomes

AF:

0.0000657

AC:

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000399

AC:

AN:

225824

AF XY:

0.0000485

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000316

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000494

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000328

AC:

AN:

1434450

Hom.:

Cov.:

AF XY:

0.0000352

AC XY:

AN XY:

710278

show subpopulations

African (AFR)

AF:

0.0000610

AC:

AN:

32772

American (AMR)

AF:

0.0000239

AC:

AN:

41926

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24696

East Asian (EAS)

AF:

0.0000509

AC:

AN:

39322

South Asian (SAS)

AF:

0.000133

AC:

AN:

82878

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51278

Middle Eastern (MID)

AF:

0.000238

AC:

AN:

4204

European-Non Finnish (NFE)

AF:

0.0000255

AC:

AN:

1098346

Other (OTH)

AF:

0.0000339

AC:

AN:

59028

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

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:

0.0000657

AC:

AN:

152206

Hom.:

Cov.:

AF XY:

0.0000672

AC XY:

AN XY:

74354

show subpopulations

African (AFR)

AF:

0.0000724

AC:

AN:

41446

American (AMR)

AF:

0.00

AC:

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000192

AC:

AN:

5196

South Asian (SAS)

AF:

0.000207

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000735

AC:

AN:

68030

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

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:

0.0000368

Hom.:

Bravo

AF:

0.0000302

ExAC

AF:

0.0000339

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Autosomal dominant nonsyndromic hearing loss 4A

Pathogenic:1

May 30, 2024

Laboratory of Prof. Karen Avraham, Tel Aviv University

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

A very rare variant predicted to cause damage by most prediction programs.

not specified

Uncertain:1

Mar 01, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.Glu1433Lys variant in MYH14 has not been previously reported in individual s with hearing loss, but has been identified in 3/59206 European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs 771755654). Although this variant has been seen in the general population, its f requency is not high enough to rule out a pathogenic role. Computational predict ion tools and conservation analyses suggest that the p.Glu1433Lys variant may im pact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of the p.Glu1433Lys variant is uncertain.

not provided

Uncertain:1

Mar 16, 2021

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.51

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.18

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.54

Eigen

Uncertain

0.32

Eigen_PC

Uncertain

0.25

FATHMM_MKL

Benign

0.66

LIST_S2

Uncertain

0.90

M_CAP

Benign

0.059

MetaRNN

Benign

0.36

MetaSVM

Uncertain

0.028

MutationAssessor

Benign

2.0

PhyloP100

7.6

PrimateAI

Pathogenic

0.86

PROVEAN

Uncertain

-3.2

REVEL

Uncertain

0.39

Sift

Uncertain

0.0050

Sift4G

Benign

0.069

Polyphen

1.0

Vest4

0.52

MutPred

0.47

Gain of MoRF binding (P = 0.0056)

MVP

0.69

MPC

0.32

ClinPred

0.54

GERP RS

2.7

Varity_R

0.057

gMVP

0.43

Mutation Taster

=81/19

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over