rs199600574

Positions:

chr19-50301724-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001145809.2(MYH14):c.5533C>T(p.Arg1845Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00104 in 1,613,852 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0021 ( 5 hom., cov: 32)

Exomes 𝑓: 0.00093 ( 14 hom. )

Consequence

MYH14
NM_001145809.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 2.72

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.010005832).

BP6

Variant 19-50301724-C-T is Benign according to our data. Variant chr19-50301724-C-T is described in ClinVar as [Benign]. Clinvar id is 504620.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00206 (314/152252) while in subpopulation NFE AF= 0.000515 (35/68016). AF 95% confidence interval is 0.000379. There are 5 homozygotes in gnomad4. There are 231 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 314 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
MYH14	NM_001145809.2 linkuse as main transcript	c.5533C>T	p.Arg1845Trp	missense_variant	40/43	ENST00000642316.2	NP_001139281.1
MYH14	NM_001077186.2 linkuse as main transcript	c.5434C>T	p.Arg1812Trp	missense_variant	39/42		NP_001070654.1
MYH14	NM_024729.4 linkuse as main transcript	c.5410C>T	p.Arg1804Trp	missense_variant	38/41		NP_079005.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYH14	ENST00000642316.2 linkuse as main transcript	c.5533C>T	p.Arg1845Trp	missense_variant	40/43		NM_001145809.2	ENSP00000493594		Q7Z406-2

Frequencies

GnomAD3 genomes

AF:

0.00206

AC:

314

AN:

152134

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0262

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000515

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00221

AC:

551

AN:

248870

Hom.:

AF XY:

0.00220

AC XY:

297

AN XY:

135032

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.0233

Gnomad NFE exome

AF:

0.000320

Gnomad OTH exome

AF:

0.00116

GnomAD4 exome

AF:

0.000934

AC:

1365

AN:

1461600

Hom.:

Cov.:

AF XY:

0.000939

AC XY:

683

AN XY:

727086

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000894

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.0198

Gnomad4 NFE exome

AF:

0.000246

Gnomad4 OTH exome

AF:

0.000431

GnomAD4 genome

AF:

0.00206

AC:

314

AN:

152252

Hom.:

Cov.:

AF XY:

0.00310

AC XY:

231

AN XY:

74446

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0262

Gnomad4 NFE

AF:

0.000515

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000432

Hom.:

Bravo

AF:

0.000106

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000473

AC:

ExAC

AF:

0.00145

AC:

175

EpiCase

AF:

0.000218

EpiControl

AF:

0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Aug 25, 2017

p.Arg1845Trp in exon 40 of MYH14: This variant is not expected to have clinical significance because it has been identified in 2.3% (590/25778) of Finnish chrom osomes including 6 homozygotes by the Genome Aggregation Database (gnomAD, http: //gnomad.broadinstitute.org; dbSNP rs199600574). -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 22, 2022

- -

MYH14-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 20, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.30

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Uncertain

0.0

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.77

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

Eigen

Benign

0.14

Eigen_PC

Benign

0.082

FATHMM_MKL

Uncertain

0.94

LIST_S2

Pathogenic

1.0

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

MetaRNN

Benign

0.010

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

MetaSVM

Uncertain

-0.022

MutationAssessor

Uncertain

2.2

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

MutationTaster

Benign

0.99

D;D;D;D

PrimateAI

Pathogenic

0.80

PROVEAN

Pathogenic

-5.7

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

REVEL

Uncertain

0.58

Sift

Uncertain

0.014

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

Sift4G

Uncertain

0.017

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

Polyphen

0.84

P;.;P;P;P;P;P

Vest4

0.87

MVP

0.79

MPC

0.26

ClinPred

0.11

GERP RS

0.27

Varity_R

0.21

gMVP

0.58

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