rs727504915

Positions:

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_001145809.2(MYH14):c.4088G>A(p.Arg1363His) variant causes a missense change. The variant allele was found at a frequency of 0.0000459 in 1,610,538 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1363C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000048 ( 0 hom. )

Consequence

MYH14
NM_001145809.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 6.14

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.24937469).

BS2

High AC in GnomAdExome4 at 70 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
MYH14	NM_001145809.2 linkuse as main transcript	c.4088G>A	p.Arg1363His	missense_variant	31/43	ENST00000642316.2
MYH14	NM_001077186.2 linkuse as main transcript	c.3989G>A	p.Arg1330His	missense_variant	30/42
MYH14	NM_024729.4 linkuse as main transcript	c.3965G>A	p.Arg1322His	missense_variant	29/41

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH14	ENST00000642316.2 linkuse as main transcript	c.4088G>A	p.Arg1363His	missense_variant	31/43		NM_001145809.2		Q7Z406-2

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152166

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:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000534

AC:

AN:

243296

Hom.:

AF XY:

0.0000531

AC XY:

AN XY:

131710

show subpopulations

Gnomad AFR exome

AF:

0.0000673

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000113

Gnomad SAS exome

AF:

0.0000679

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000725

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000480

AC:

AN:

1458372

Hom.:

Cov.:

AF XY:

0.0000414

AC XY:

AN XY:

725066

show subpopulations

Gnomad4 AFR exome

AF:

0.000209

Gnomad4 AMR exome

AF:

0.0000226

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000505

Gnomad4 SAS exome

AF:

0.0000703

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000414

Gnomad4 OTH exome

AF:

0.000116

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152166

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74326

show subpopulations

Gnomad4 AFR

AF:

0.0000724

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000302

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000519

AC:

ExAC

AF:

0.0000412

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jan 02, 2014

The Arg1363His variant in MYH14 has not been previously reported in individuals with hearing loss or in large population studies. Computational analyses (bioche mical amino acid properties, conservation, AlignGVGD, PolyPhen2, and SIFT) sugge st that the Arg1363His variant may impact the protein, though this information i s not predictive enough to determine pathogenicity. In summary, additional info rmation is needed to determine the clinical significance of this variant. -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 09, 2023

The c.3965G>A (p.R1322H) alteration is located in exon 29 (coding exon 28) of the MYH14 gene. This alteration results from a G to A substitution at nucleotide position 3965, causing the arginine (R) at amino acid position 1322 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Autosomal dominant nonsyndromic hearing loss 4A;C3280556:Peripheral neuropathy-myopathy-hoarseness-hearing loss syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

New York Genome Center

Apr 06, 2023

The c.4088G>A p.(Arg1363His) variant identified in MYH14 has not previously been reported in the affected individuals in the literature and it has been deposited in ClinVar [ClinVar ID: 179510] as a Variant of Uncertain Significance (2 submissions). The c.4088G>A variant is observed in 23 out of ~582,722 heterozygous alleles (0.0039% minor allele frequency with 0 homozygotes) in population databases (gnomAD v2.1.1 and v3.1.2, TOPMed Freeze 8). The c.4088G>A variant is located in exon 31 of this 43-exon gene and is predicted to replace a moderately conserved arginine amino acid with histidine at position 1363 in the encoded protein. In silico predictions are not in favor of the damaging effect for the p.(Arg1363His) variant [REVEL = 0.388)]; however, there are no functional studiesto support or refute these predictions. A different missense variant p.(Arg1363Cys) affecting the same amino acid residue has been reported in ClinVar [ClinVar ID:1195791] as a Variant of Uncertain Significance (1 submission).Based on available evidence, this c.4088G>A p.(Arg1363His) variant identified in MYH14 is classified as a Variant of Uncertain Significance. -

Hearing impairment

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Department of Otolaryngology – Head & Neck Surgery, Cochlear Implant Center

Apr 12, 2021

PP3_Supporting, BS2_Strong -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Benign

-0.28

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.37

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

Eigen

Uncertain

0.45

Eigen_PC

Uncertain

0.39

FATHMM_MKL

Benign

0.64

LIST_S2

Uncertain

0.97

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

M_CAP

Uncertain

0.20

MetaRNN

Benign

0.25

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

MetaSVM

Uncertain

0.019

MutationAssessor

Benign

1.1

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

MutationTaster

Benign

0.70

D;D;D;D

PrimateAI

Benign

0.47

PROVEAN

Benign

-2.1

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

REVEL

Uncertain

0.39

Sift

Uncertain

0.011

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

Sift4G

Uncertain

0.056

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

Polyphen

0.99

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

Vest4

0.22

MutPred

0.39

.;.;Loss of MoRF binding (P = 0.0174);.;.;Loss of MoRF binding (P = 0.0174);.;

MVP

0.66

MPC

0.68

ClinPred

0.28

GERP RS

3.4

Varity_R

0.070

gMVP

0.23

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over