rs370256265

Positions:

chr19-50275998-G-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BS1_SupportingBS2

The NM_001145809.2(MYH14):c.3475G>T(p.Asp1159Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000316 in 1,612,258 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00034 ( 2 hom. )

Consequence

MYH14
NM_001145809.2 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 9.52

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 -5 ACMG points.

BS1

Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.000338 (493/1460038) while in subpopulation NFE AF= 0.000437 (486/1111308). AF 95% confidence interval is 0.000405. There are 2 homozygotes in gnomad4_exome. There are 223 alleles in male gnomad4_exome subpopulation. Median coverage is 32. 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 16 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
MYH14	NM_001145809.2 linkuse as main transcript	c.3475G>T	p.Asp1159Tyr	missense_variant	28/43	ENST00000642316.2	NP_001139281.1
MYH14	NM_001077186.2 linkuse as main transcript	c.3376G>T	p.Asp1126Tyr	missense_variant	27/42		NP_001070654.1
MYH14	NM_024729.4 linkuse as main transcript	c.3352G>T	p.Asp1118Tyr	missense_variant	26/41		NP_079005.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYH14	ENST00000642316.2 linkuse as main transcript	c.3475G>T	p.Asp1159Tyr	missense_variant	28/43		NM_001145809.2	ENSP00000493594		Q7Z406-2

Frequencies

GnomAD3 genomes

AF:

0.000105

AC:

AN:

152220

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

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:

0.000162

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000946

AC:

AN:

243084

Hom.:

AF XY:

0.000105

AC XY:

AN XY:

132850

show subpopulations

Gnomad AFR exome

AF:

0.000206

Gnomad AMR exome

AF:

0.00

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:

0.000174

Gnomad OTH exome

AF:

0.000169

GnomAD4 exome

AF:

0.000338

AC:

493

AN:

1460038

Hom.:

Cov.:

AF XY:

0.000307

AC XY:

223

AN XY:

726214

show subpopulations

Gnomad4 AFR exome

AF:

0.0000598

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000437

Gnomad4 OTH exome

AF:

0.0000829

GnomAD4 genome

AF:

0.000105

AC:

AN:

152220

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74358

show subpopulations

Gnomad4 AFR

AF:

0.000121

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:

0.000162

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000197

Hom.:

Bravo

AF:

0.000151

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000365

AC:

ExAC

AF:

0.000108

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.000237

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

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

Sep 04, 2013

The Asp1159Tyr variant in MYH14 has not been reported in individuals with hearin g loss, but has been identified in 0.04% (3/8230) of European American chromosom es by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS, dbSN P rs370256265). Although this variant was identified in the general population, its frequency is not high enough to rule out a pathogenic role. Computational an alyses (biochemical amino acid properties, conservation, AlignGVGD, PolyPhen2, a nd SIFT) do not provide strong support for or against an impact to the protein. In summary,additional information is needed to fully assess the clinical signifi cance of the Asp1159Tyr variant. -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 30, 2021

The c.3352G>T (p.D1118Y) alteration is located in exon 26 (coding exon 25) of the MYH14 gene. This alteration results from a G to T substitution at nucleotide position 3352, causing the aspartic acid (D) at amino acid position 1118 to be replaced by a tyrosine (Y). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Oct 02, 2024

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.33

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Benign

-0.13

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.80

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

Eigen

Uncertain

0.61

Eigen_PC

Uncertain

0.56

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.85

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

M_CAP

Uncertain

0.18

MetaRNN

Uncertain

0.74

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

MetaSVM

Uncertain

0.53

MutationAssessor

Benign

2.0

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

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Uncertain

0.66

PROVEAN

Pathogenic

-4.7

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

REVEL

Pathogenic

0.68

Sift

Pathogenic

0.0

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

Sift4G

Pathogenic

0.0010

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

Polyphen

0.96

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

Vest4

0.42

MVP

0.62

MPC

0.46

ClinPred

0.71

GERP RS

4.5

Varity_R

0.29

gMVP

0.49

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