19-50210370-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM1PM2

The NM_001145809.2(MYH14):​c.5C>T​(p.Ala2Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000252 in 1,587,086 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. A2E) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

MYH14
NM_001145809.2 missense

Scores

4
7
8

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 1.67

Publications

0 publications found
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 Gene-Disease associations (from GenCC):
  • autosomal dominant nonsyndromic hearing loss 4A
    Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Ambry Genetics
  • peripheral neuropathy-myopathy-hoarseness-hearing loss syndrome
    Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)
  • nonsyndromic genetic hearing loss
    Inheritance: AD Classification: MODERATE Submitted by: ClinGen
  • autosomal dominant nonsyndromic hearing loss
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM1
In a modified_residue N-acetylalanine (size 0) in uniprot entity MYH14_HUMAN
PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
MYH14NM_001145809.2 linkc.5C>T p.Ala2Val missense_variant Exon 2 of 43 ENST00000642316.2 NP_001139281.1 Q7Z406-2A1L2Z2B3KWH4
MYH14NM_001077186.2 linkc.5C>T p.Ala2Val missense_variant Exon 2 of 42 NP_001070654.1 Q7Z406-6B3KWH4
MYH14NM_024729.4 linkc.5C>T p.Ala2Val missense_variant Exon 2 of 41 NP_079005.3 Q7Z406-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
MYH14ENST00000642316.2 linkc.5C>T p.Ala2Val missense_variant Exon 2 of 43 NM_001145809.2 ENSP00000493594.1 Q7Z406-2

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152158
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
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
GnomAD2 exomes
AF:
0.00000486
AC:
1
AN:
205706
AF XY:
0.00000877
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000112
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000209
AC:
3
AN:
1434928
Hom.:
0
Cov.:
31
AF XY:
0.00000421
AC XY:
3
AN XY:
712670
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
31052
American (AMR)
AF:
0.00
AC:
0
AN:
42468
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
25398
East Asian (EAS)
AF:
0.00
AC:
0
AN:
37628
South Asian (SAS)
AF:
0.00
AC:
0
AN:
82850
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
50550
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5708
European-Non Finnish (NFE)
AF:
0.00000273
AC:
3
AN:
1100236
Other (OTH)
AF:
0.00
AC:
0
AN:
59038
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.442
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152158
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74324
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
41458
American (AMR)
AF:
0.00
AC:
0
AN:
15284
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3468
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5172
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4836
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10592
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.0000147
AC:
1
AN:
68032
Other (OTH)
AF:
0.00
AC:
0
AN:
2088
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.575
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Alfa
AF:
0.00
Hom.:
0
Bravo
AF:
0.0000113
ExAC
AF:
0.00000850
AC:
1

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Nonsyndromic Hearing Loss, Dominant Uncertain:1
Jun 14, 2016
Illumina Laboratory Services, Illumina
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

not provided Uncertain:1
Sep 05, 2024
GeneDx
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter 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
Uncertain
0.50
BayesDel_addAF
Uncertain
0.089
D
BayesDel_noAF
Benign
-0.11
CADD
Pathogenic
26
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.10
.;.;T;.;T;.;.;T
Eigen
Benign
0.015
Eigen_PC
Benign
0.13
FATHMM_MKL
Uncertain
0.91
D
LIST_S2
Benign
0.79
.;T;T;.;T;T;T;.
M_CAP
Uncertain
0.091
D
MetaRNN
Uncertain
0.56
D;D;D;D;D;D;D;D
MetaSVM
Uncertain
-0.052
T
MutationAssessor
Benign
1.4
L;L;L;L;.;L;.;L
PhyloP100
1.7
PrimateAI
Pathogenic
0.81
D
PROVEAN
Benign
-0.48
.;N;N;.;.;.;.;.
REVEL
Uncertain
0.47
Sift
Pathogenic
0.0
.;D;D;.;.;.;.;.
Sift4G
Pathogenic
0.0
D;D;D;.;D;D;.;D
Polyphen
0.60
P;P;P;P;.;P;.;P
Vest4
0.47
MVP
0.56
MPC
1.3
ClinPred
0.71
D
GERP RS
4.5
PromoterAI
-0.072
Neutral
Varity_R
0.069
gMVP
0.49
Mutation Taster
=91/9
polymorphism

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

Other links and lift over

dbSNP: rs750407725; hg19: chr19-50713627; API