chr19-50244277-G-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 1P and 13B. PP3BP4_StrongBP6BS1BS2

The NM_001145809.2(MYH14):​c.1150G>T​(p.Gly384Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00374 in 1,613,848 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0030 ( 0 hom., cov: 31)
Exomes 𝑓: 0.0038 ( 22 hom. )

Consequence

MYH14
NM_001145809.2 missense

Scores

13
4
2

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:1B:12

Conservation

PhyloP100: 9.88
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

PP3
Multiple lines of computational evidence support a deleterious effect 9: AlphaMissense, BayesDel_addAF, BayesDel_noAF, Cadd, Eigen, MutationAssessor, phyloP100way_vertebrate, PROVEAN, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
BP4
Computational evidence support a benign effect (MetaRNN=0.06556776).
BP6
Variant 19-50244277-G-T is Benign according to our data. Variant chr19-50244277-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2199.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=2, Likely_benign=8}. Variant chr19-50244277-G-T is described in Lovd as [Likely_benign].
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.003 (457/152178) while in subpopulation NFE AF= 0.00434 (295/68008). AF 95% confidence interval is 0.00393. There are 0 homozygotes in gnomad4. There are 206 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
BS2
High AC in GnomAd4 at 457 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
MYH14NM_001145809.2 linkc.1150G>T p.Gly384Cys missense_variant Exon 11 of 43 ENST00000642316.2 NP_001139281.1 Q7Z406-2A1L2Z2B3KWH4
MYH14NM_001077186.2 linkc.1150G>T p.Gly384Cys missense_variant Exon 11 of 42 NP_001070654.1 Q7Z406-6B3KWH4
MYH14NM_024729.4 linkc.1126G>T p.Gly376Cys missense_variant Exon 10 of 41 NP_079005.3 Q7Z406-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
MYH14ENST00000642316.2 linkc.1150G>T p.Gly384Cys missense_variant Exon 11 of 43 NM_001145809.2 ENSP00000493594.1 Q7Z406-2

Frequencies

GnomAD3 genomes
AF:
0.00301
AC:
457
AN:
152060
Hom.:
0
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.000797
Gnomad AMI
AF:
0.00658
Gnomad AMR
AF:
0.00321
Gnomad ASJ
AF:
0.0141
Gnomad EAS
AF:
0.000193
Gnomad SAS
AF:
0.00208
Gnomad FIN
AF:
0.0000944
Gnomad MID
AF:
0.0127
Gnomad NFE
AF:
0.00434
Gnomad OTH
AF:
0.00431
GnomAD3 exomes
AF:
0.00304
AC:
757
AN:
248750
Hom.:
5
AF XY:
0.00321
AC XY:
434
AN XY:
135002
show subpopulations
Gnomad AFR exome
AF:
0.000905
Gnomad AMR exome
AF:
0.00243
Gnomad ASJ exome
AF:
0.0134
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00157
Gnomad FIN exome
AF:
0.000232
Gnomad NFE exome
AF:
0.00396
Gnomad OTH exome
AF:
0.00413
GnomAD4 exome
AF:
0.00382
AC:
5578
AN:
1461670
Hom.:
22
Cov.:
32
AF XY:
0.00380
AC XY:
2761
AN XY:
727118
show subpopulations
Gnomad4 AFR exome
AF:
0.000836
Gnomad4 AMR exome
AF:
0.00206
Gnomad4 ASJ exome
AF:
0.0117
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00192
Gnomad4 FIN exome
AF:
0.000262
Gnomad4 NFE exome
AF:
0.00418
Gnomad4 OTH exome
AF:
0.00404
GnomAD4 genome
AF:
0.00300
AC:
457
AN:
152178
Hom.:
0
Cov.:
31
AF XY:
0.00277
AC XY:
206
AN XY:
74386
show subpopulations
Gnomad4 AFR
AF:
0.000795
Gnomad4 AMR
AF:
0.00321
Gnomad4 ASJ
AF:
0.0141
Gnomad4 EAS
AF:
0.000193
Gnomad4 SAS
AF:
0.00208
Gnomad4 FIN
AF:
0.0000944
Gnomad4 NFE
AF:
0.00434
Gnomad4 OTH
AF:
0.00426
Alfa
AF:
0.00433
Hom.:
3
Bravo
AF:
0.00301
TwinsUK
AF:
0.00324
AC:
12
ALSPAC
AF:
0.00545
AC:
21
ESP6500AA
AF:
0.000702
AC:
3
ESP6500EA
AF:
0.00389
AC:
33
ExAC
AF:
0.00285
AC:
345
Asia WGS
AF:
0.000866
AC:
3
AN:
3478
EpiCase
AF:
0.00474
EpiControl
AF:
0.00557

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:1Benign:12
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Benign:8
-
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Oct 26, 2023
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jan 05, 2017
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Feb 21, 2020
GeneDx
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 27391121, 25262649, 30622556, 15015131, 27884173, 25098841, 30245029, 31898538) -

Jul 08, 2019
Athena Diagnostics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jan 20, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
Clinical Genetics, Academic Medical Center
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Jan 01, 2025
CeGaT Center for Human Genetics Tuebingen
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

MYH14: BS2 -

not specified Benign:3
Sep 13, 2016
Eurofins Ntd Llc (ga)
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jul 05, 2017
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

p.Gly384Cys in exon 11 of MYH14: This variant is not expected to have clinical s ignificance, because it has been identified in 1.3% (136/10142) of Ashkenazi Jew ish chromosomes including 1 homozygote by the Genome Aggregation Database (gnomA D, http://gnomad.broadinstitute.org/; dbSNP rs119103280). Although this variant has been reported as a de novo variant in one individual with moderate sensorine ural hearing loss (Donaudy 2004), the evidence is not sufficient to establish ca usality. -

Apr 27, 2019
Genomic Research Center, Shahid Beheshti University of Medical Sciences
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Autosomal dominant nonsyndromic hearing loss 4A Pathogenic:1Uncertain:1
Apr 27, 2017
Illumina Laboratory Services, Illumina
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Apr 01, 2004
OMIM
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

- -

Peripheral neuropathy-myopathy-hoarseness-hearing loss syndrome Benign:1
May 04, 2023
Molecular Genetics, Royal Melbourne Hospital
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

European Non-Finnish population allele frequency is 0.3994% (rs119103280, 511/127.956 alleles, 1 homozygotes in gnomAD v2.1). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.5.1, this variant is classified as LIKELY BENIGN. Following criteria are met: BS1 -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.98
BayesDel_addAF
Pathogenic
0.24
D
BayesDel_noAF
Pathogenic
0.57
CADD
Pathogenic
26
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.94
.;.;D;.;D;.;D
Eigen
Pathogenic
0.84
Eigen_PC
Uncertain
0.62
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Pathogenic
0.98
.;D;D;.;D;D;.
M_CAP
Uncertain
0.16
D
MetaRNN
Benign
0.066
T;T;T;T;T;T;T
MetaSVM
Pathogenic
0.84
D
MutationAssessor
Pathogenic
4.2
.;.;H;.;.;.;H
PrimateAI
Uncertain
0.65
T
PROVEAN
Pathogenic
-7.9
.;D;D;.;.;.;.
REVEL
Pathogenic
0.93
Sift
Pathogenic
0.0
.;D;D;.;.;.;.
Sift4G
Pathogenic
0.0010
D;D;D;.;D;D;D
Polyphen
1.0
D;D;D;D;.;D;D
Vest4
0.91
MVP
0.97
MPC
1.4
ClinPred
0.12
T
GERP RS
3.4
Varity_R
0.61
gMVP
0.87

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.

Other links and lift over

dbSNP: rs119103280; hg19: chr19-50747534; API