rs374883445

Positions:

chr19-50268174-G-A

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBS1_SupportingBS2

The NM_001145809.2(MYH14):c.2840G>A(p.Arg947His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000465 in 1,546,824 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. R947C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00016 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000034 ( 0 hom. )

Consequence

MYH14
NM_001145809.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 2.33

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 Benign. Variant got -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.2121031).

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000164 (25/152308) while in subpopulation AFR AF= 0.000529 (22/41572). AF 95% confidence interval is 0.000358. There are 0 homozygotes in gnomad4. There are 15 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High AC in GnomAd4 at 25 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
MYH14	NM_001145809.2 linkuse as main transcript	c.2840G>A	p.Arg947His	missense_variant	24/43	ENST00000642316.2
MYH14	NM_001077186.2 linkuse as main transcript	c.2741G>A	p.Arg914His	missense_variant	23/42
MYH14	NM_024729.4 linkuse as main transcript	c.2717G>A	p.Arg906His	missense_variant	22/41

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH14	ENST00000642316.2 linkuse as main transcript	c.2840G>A	p.Arg947His	missense_variant	24/43		NM_001145809.2		Q7Z406-2

Frequencies

GnomAD3 genomes

AF:

0.000171

AC:

AN:

152190

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000555

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000131

AC:

AN:

152494

Hom.:

AF XY:

0.000111

AC XY:

AN XY:

81058

show subpopulations

Gnomad AFR exome

AF:

0.000996

Gnomad AMR exome

AF:

0.000404

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000459

GnomAD4 exome

AF:

0.0000337

AC:

AN:

1394516

Hom.:

Cov.:

AF XY:

0.0000320

AC XY:

AN XY:

687882

show subpopulations

Gnomad4 AFR exome

AF:

0.000475

Gnomad4 AMR exome

AF:

0.000391

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000252

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000834

Gnomad4 OTH exome

AF:

0.000121

GnomAD4 genome

AF:

0.000164

AC:

AN:

152308

Hom.:

Cov.:

AF XY:

0.000201

AC XY:

AN XY:

74486

show subpopulations

Gnomad4 AFR

AF:

0.000529

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000129

Hom.:

Bravo

AF:

0.000185

ESP6500AA

AF:

0.000733

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000282

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Apr 18, 2023	In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MYH14 protein function. ClinVar contains an entry for this variant (Variation ID: 164181). This variant has not been reported in the literature in individuals affected with MYH14-related conditions. This variant is present in population databases (rs374883445, gnomAD 0.08%), and has an allele count higher than expected for a pathogenic variant. This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 906 of the MYH14 protein (p.Arg906His). -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

May 20, 2014

The Arg947His in MYH14 has not been reported in individuals with hearing loss, b ut has been identified in 0.07% (3/4092) of African American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu). The arginine (Arg ) at position 947 is conserved in mammals, but not in evolutionarily distant spe cies. This raises the possibility that a change at this position may be tolerate d. Other computational prediction tools suggest that the Arg947His variant may i mpact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of the Arg947His variant i s uncertain. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.21

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.60

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

Eigen

Uncertain

0.47

Eigen_PC

Uncertain

0.39

FATHMM_MKL

Benign

0.26

LIST_S2

Pathogenic

0.98

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

M_CAP

Pathogenic

0.74

MetaRNN

Benign

0.21

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

MetaSVM

Uncertain

0.098

MutationAssessor

Uncertain

2.0

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

MutationTaster

Benign

0.88

D;D;D;D

PrimateAI

Uncertain

0.67

PROVEAN

Uncertain

-3.4

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

REVEL

Uncertain

0.47

Sift

Uncertain

0.0010

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

Sift4G

Uncertain

0.0020

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

Polyphen

1.0

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

Vest4

0.25

MVP

0.74

MPC

1.4

ClinPred

0.14

GERP RS

3.9

Varity_R

0.045

gMVP

0.30

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