19-50252726-C-T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001145809.2(MYH14):​c.1918C>T​(p.Arg640Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000203 in 1,595,570 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R640G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00024 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00020 ( 2 hom. )

Consequence

MYH14
NM_001145809.2 missense

Scores

8
11

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:4

Conservation

PhyloP100: 1.99

Publications

1 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: Benign. The variant received -13 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.030691683).
BP6
Variant 19-50252726-C-T is Benign according to our data. Variant chr19-50252726-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 178416.We mark this variant Likely_benign, oryginal submission is: [Conflicting_classifications_of_pathogenicity].
BS1
Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000236 (36/152280) while in subpopulation SAS AF = 0.00124 (6/4820). AF 95% confidence interval is 0.000813. There are 0 homozygotes in GnomAd4. There are 21 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
BS2
High AC in GnomAd4 at 36 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
MYH14NM_001145809.2 linkc.1918C>T p.Arg640Trp missense_variant Exon 16 of 43 ENST00000642316.2 NP_001139281.1 Q7Z406-2A1L2Z2B3KWH4
MYH14NM_001077186.2 linkc.1918C>T p.Arg640Trp missense_variant Exon 16 of 42 NP_001070654.1 Q7Z406-6B3KWH4
MYH14NM_024729.4 linkc.1894C>T p.Arg632Trp missense_variant Exon 15 of 41 NP_079005.3 Q7Z406-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
MYH14ENST00000642316.2 linkc.1918C>T p.Arg640Trp missense_variant Exon 16 of 43 NM_001145809.2 ENSP00000493594.1 Q7Z406-2

Frequencies

GnomAD3 genomes
AF:
0.000237
AC:
36
AN:
152162
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000121
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00124
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00124
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000735
Gnomad OTH
AF:
0.000479
GnomAD2 exomes
AF:
0.000449
AC:
98
AN:
218474
AF XY:
0.000568
show subpopulations
Gnomad AFR exome
AF:
0.000159
Gnomad AMR exome
AF:
0.000322
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000819
Gnomad OTH exome
AF:
0.000362
GnomAD4 exome
AF:
0.000200
AC:
288
AN:
1443290
Hom.:
2
Cov.:
30
AF XY:
0.000242
AC XY:
173
AN XY:
716216
show subpopulations
African (AFR)
AF:
0.000303
AC:
10
AN:
32976
American (AMR)
AF:
0.000310
AC:
13
AN:
41952
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
25774
East Asian (EAS)
AF:
0.0000259
AC:
1
AN:
38646
South Asian (SAS)
AF:
0.00197
AC:
164
AN:
83060
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
51888
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5756
European-Non Finnish (NFE)
AF:
0.0000770
AC:
85
AN:
1103494
Other (OTH)
AF:
0.000251
AC:
15
AN:
59744
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.476
Heterozygous variant carriers
0
14
27
41
54
68
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Exome Hom
Variant carriers
0
10
20
30
40
50
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.000236
AC:
36
AN:
152280
Hom.:
0
Cov.:
32
AF XY:
0.000282
AC XY:
21
AN XY:
74454
show subpopulations
African (AFR)
AF:
0.000120
AC:
5
AN:
41548
American (AMR)
AF:
0.00124
AC:
19
AN:
15288
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3472
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5182
South Asian (SAS)
AF:
0.00124
AC:
6
AN:
4820
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10620
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
294
European-Non Finnish (NFE)
AF:
0.0000735
AC:
5
AN:
68036
Other (OTH)
AF:
0.000474
AC:
1
AN:
2108
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.512
Heterozygous variant carriers
0
2
4
6
8
10
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.000110
Hom.:
0
Bravo
AF:
0.000170
ESP6500AA
AF:
0.000231
AC:
1
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.000421
AC:
51
Asia WGS
AF:
0.00260
AC:
9
AN:
3478

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:4
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Benign:3
Jan 22, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Nov 01, 2023
Revvity Omics, Revvity
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Jun 18, 2020
GeneDx
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

Has not been previously published as pathogenic or benign to our knowledge -

not specified Uncertain:1
Jul 03, 2018
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The p.Arg640Trp variant in MYH14 has been previously reported by our laboratory in 1 individual with hearing loss, and it has also been identified in 0.28% (75/ 26920) of South Asian chromosomes including 1 homozygote by the Genome Aggregati on Database (gnomAD, http://gnomad.broadinstitute.org). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the p.Arg640Trp variant is uncertain. ACMG/AMP Criteria applied: BS1_Supporting. -

MYH14-related disorder Benign:1
Nov 22, 2019
PreventionGenetics, part of Exact Sciences
Significance:Likely benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

This variant is classified as likely 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
0.15
BayesDel_addAF
Benign
-0.25
T
BayesDel_noAF
Benign
-0.14
CADD
Uncertain
23
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.65
.;.;D;.;D;.;D
Eigen
Benign
-0.14
Eigen_PC
Benign
-0.083
FATHMM_MKL
Benign
0.69
D
LIST_S2
Uncertain
0.96
.;D;D;.;D;D;.
M_CAP
Uncertain
0.16
D
MetaRNN
Benign
0.031
T;T;T;T;T;T;T
MetaSVM
Uncertain
0.25
D
MutationAssessor
Benign
1.3
.;.;L;.;.;.;L
PhyloP100
2.0
PrimateAI
Benign
0.42
T
PROVEAN
Uncertain
-4.0
.;D;D;.;.;.;.
REVEL
Uncertain
0.46
Sift
Benign
0.044
.;D;D;.;.;.;.
Sift4G
Uncertain
0.0060
D;D;D;.;D;D;D
Polyphen
0.070
B;B;B;B;.;B;B
Vest4
0.50
MVP
0.77
MPC
0.48
ClinPred
0.048
T
GERP RS
2.0
Varity_R
0.17
gMVP
0.59
Mutation Taster
=90/10
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: rs376267080; hg19: chr19-50755983; COSMIC: COSV51816114; COSMIC: COSV51816114; API