Genetic Variant MYH14:p.Arg867Leu (chr19-50263326-G-T) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4BS2

The NM_001145809.2(MYH14):c.2600G>T(p.Arg867Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000425 in 1,410,142 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R867C) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000043 ( 0 hom. )

Consequence

MYH14
NM_001145809.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.88

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: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.2778369).

BS2

High AC in GnomAdExome4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
MYH14	NM_001145809.2 link	c.2600G>T	p.Arg867Leu	missense_variant	Exon 22 of 43	ENST00000642316.2	NP_001139281.1
MYH14	NM_001077186.2 link	c.2501G>T	p.Arg834Leu	missense_variant	Exon 21 of 42		NP_001070654.1
MYH14	NM_024729.4 link	c.2477G>T	p.Arg826Leu	missense_variant	Exon 20 of 41		NP_079005.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYH14	ENST00000642316.2 link	c.2600G>T	p.Arg867Leu	missense_variant	Exon 22 of 43		NM_001145809.2	ENSP00000493594.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000554

AC:

AN:

180606

AF XY:

0.0000103

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000774

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000425

AC:

AN:

1410142

Hom.:

Cov.:

AF XY:

0.00000430

AC XY:

AN XY:

697202

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31944

American (AMR)

AF:

0.00

AC:

AN:

37334

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25096

East Asian (EAS)

AF:

0.00

AC:

AN:

36822

South Asian (SAS)

AF:

0.00

AC:

AN:

79516

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50122

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5642

European-Non Finnish (NFE)

AF:

0.00000553

AC:

AN:

1085278

Other (OTH)

AF:

0.00

AC:

AN:

58388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

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

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.43

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Benign

-0.23

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.60

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

Eigen

Benign

-0.33

Eigen_PC

Benign

-0.24

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.96

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

M_CAP

Benign

0.052

MetaRNN

Benign

0.28

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

MetaSVM

Benign

-0.94

MutationAssessor

Benign

0.31

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

PhyloP100

1.9

PrimateAI

Uncertain

0.69

PROVEAN

Pathogenic

-6.2

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

REVEL

Uncertain

0.30

Sift

Benign

0.10

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

Sift4G

Benign

0.27

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

Polyphen

0.21

B;B;B;B;.;B;B

Vest4

0.53

MutPred

0.46

.;.;Loss of solvent accessibility (P = 0.0299);.;.;.;Loss of solvent accessibility (P = 0.0299);

MVP

0.91

MPC

0.81

ClinPred

0.41

GERP RS

3.0

Varity_R

0.16

gMVP

0.76

Mutation Taster

=87/13

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over