Genetic Variant MYH14:p.Arg1816Ser (chr19-50293664-C-A) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_001145809.2(MYH14):c.5446C>A(p.Arg1816Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000000694 in 1,441,800 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. R1816H) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

MYH14
NM_001145809.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.86

Publications

1 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: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.864

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH14	NM_001145809.2 link	c.5446C>A	p.Arg1816Ser	missense_variant	Exon 39 of 43	ENST00000642316.2	NP_001139281.1	Q7Z406-2A1L2Z2B3KWH4
MYH14	NM_001077186.2 link	c.5347C>A	p.Arg1783Ser	missense_variant	Exon 38 of 42		NP_001070654.1	Q7Z406-6B3KWH4
MYH14	NM_024729.4 link	c.5323C>A	p.Arg1775Ser	missense_variant	Exon 37 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.5446C>A	p.Arg1816Ser	missense_variant	Exon 39 of 43		NM_001145809.2	ENSP00000493594.1		Q7Z406-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000427

AC:

AN:

234406

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000939

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.94e-7

AC:

AN:

1441800

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

715298

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33122

American (AMR)

AF:

0.00

AC:

AN:

42168

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24742

East Asian (EAS)

AF:

0.00

AC:

AN:

39432

South Asian (SAS)

AF:

0.00

AC:

AN:

83290

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52798

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5560

European-Non Finnish (NFE)

AF:

9.08e-7

AC:

AN:

1101190

Other (OTH)

AF:

0.00

AC:

AN:

59498

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000254

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.87

BayesDel_addAF

Uncertain

0.10

BayesDel_noAF

Benign

-0.090

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.57

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

Eigen

Uncertain

0.68

Eigen_PC

Uncertain

0.60

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.99

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

M_CAP

Uncertain

0.22

MetaRNN

Pathogenic

0.86

D;D;D;D;D;D;D

MetaSVM

Uncertain

0.79

MutationAssessor

Uncertain

2.3

.;.;.;M;.;.;M

PhyloP100

4.9

PrimateAI

Benign

0.34

PROVEAN

Pathogenic

-4.5

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

REVEL

Uncertain

0.57

Sift

Uncertain

0.0010

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

Sift4G

Uncertain

0.0030

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

Polyphen

0.98

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

Vest4

0.54

MutPred

0.71

.;.;.;Gain of phosphorylation at R1775 (P = 0.0262);.;.;Gain of phosphorylation at R1775 (P = 0.0262);

MVP

0.61

MPC

0.52

ClinPred

0.99

GERP RS

3.7

Varity_R

0.36

gMVP

0.45

Mutation Taster

=65/35

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over