NM_016239.4:c.215G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_016239.4(MYO15A):​c.215G>A​(p.Arg72His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000105 in 1,612,530 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. R72R) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000089 ( 0 hom. )

Consequence

MYO15A
NM_016239.4 missense

Scores

2
9
8

Clinical Significance

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

Conservation

PhyloP100: 2.70

Publications

0 publications found
Variant links:
Genes affected
MYO15A (HGNC:7594): (myosin XVA) This gene encodes an unconventional myosin. This protein differs from other myosins in that it has a long N-terminal extension preceding the conserved motor domain. Studies in mice suggest that this protein is necessary for actin organization in the hair cells of the cochlea. Mutations in this gene have been associated with profound, congenital, neurosensory, nonsyndromal deafness. This gene is located within the Smith-Magenis syndrome region on chromosome 17. Read-through transcripts containing an upstream gene and this gene have been identified, but they are not thought to encode a fusion protein. Several alternatively spliced transcript variants have been described, but their full length sequences have not been determined. [provided by RefSeq, Jul 2008]
MYO15A Gene-Disease associations (from GenCC):
  • autosomal recessive nonsyndromic hearing loss 3
    Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), PanelApp Australia
  • nonsyndromic genetic hearing loss
    Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
  • hearing loss, autosomal recessive
    Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.16872343).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
MYO15ANM_016239.4 linkc.215G>A p.Arg72His missense_variant Exon 2 of 66 ENST00000647165.2 NP_057323.3 Q9UKN7-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
MYO15AENST00000647165.2 linkc.215G>A p.Arg72His missense_variant Exon 2 of 66 NM_016239.4 ENSP00000495481.1 Q9UKN7-1
MYO15AENST00000583079.1 linkn.-153G>A upstream_gene_variant 6

Frequencies

GnomAD3 genomes
AF:
0.0000263
AC:
4
AN:
152180
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000196
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:
0.0000327
AC:
8
AN:
244784
AF XY:
0.0000149
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000233
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000890
AC:
13
AN:
1460350
Hom.:
0
Cov.:
35
AF XY:
0.00000551
AC XY:
4
AN XY:
726476
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33472
American (AMR)
AF:
0.000269
AC:
12
AN:
44646
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26108
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39690
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86204
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
52246
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5766
European-Non Finnish (NFE)
AF:
8.99e-7
AC:
1
AN:
1111858
Other (OTH)
AF:
0.00
AC:
0
AN:
60360
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.506
Heterozygous variant carriers
0
1
2
3
4
5
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome 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
GnomAD4 genome
AF:
0.0000263
AC:
4
AN:
152180
Hom.:
0
Cov.:
33
AF XY:
0.0000269
AC XY:
2
AN XY:
74342
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
41458
American (AMR)
AF:
0.000196
AC:
3
AN:
15272
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3466
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5178
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4832
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10622
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.0000147
AC:
1
AN:
68034
Other (OTH)
AF:
0.00
AC:
0
AN:
2090
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.450
Heterozygous variant carriers
0
1
1
2
2
3
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:
0.00
Hom.:
0
Bravo
AF:
0.00000756
ExAC
AF:
0.0000166
AC:
2

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Uncertain:1
Mar 16, 2017
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The p.Arg72His variant in MYO15A has not been previously reported in individuals with hearing loss, but has been identified in 11/34300 Latino chromosomes by th e Genome Aggregation Database (gnomAD, http://gnomAD.broadinstitute.org; dbSNP r s759523877). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. Computational predic tion tools do not provide strong support for or against an impact to the protein . In summary, the clinical significance of the p.Arg72His variant is uncertain. -

Inborn genetic diseases Uncertain:1
Dec 28, 2022
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The c.215G>A (p.R72H) alteration is located in exon 2 (coding exon 1) of the MYO15A gene. This alteration results from a G to A substitution at nucleotide position 215, causing the arginine (R) at amino acid position 72 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1
Aug 15, 2022
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 72 of the MYO15A protein (p.Arg72His). This variant is present in population databases (rs759523877, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with MYO15A-related conditions. ClinVar contains an entry for this variant (Variation ID: 517275). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt MYO15A protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.48
BayesDel_addAF
Benign
-0.095
T
BayesDel_noAF
Uncertain
-0.080
CADD
Pathogenic
29
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.029
T;T;T
Eigen
Benign
0.18
Eigen_PC
Uncertain
0.30
FATHMM_MKL
Uncertain
0.95
D
LIST_S2
Benign
0.80
T;.;T
M_CAP
Uncertain
0.12
D
MetaRNN
Benign
0.17
T;T;T
MetaSVM
Uncertain
-0.076
T
MutationAssessor
Benign
0.34
.;N;N
PhyloP100
2.7
PrimateAI
Uncertain
0.69
T
PROVEAN
Benign
-2.1
.;N;.
REVEL
Uncertain
0.39
Sift
Uncertain
0.0010
.;D;.
Sift4G
Pathogenic
0.0010
D;D;.
Polyphen
0.65
.;P;P
Vest4
0.43
MutPred
0.22
Gain of relative solvent accessibility (P = 0.0522);Gain of relative solvent accessibility (P = 0.0522);Gain of relative solvent accessibility (P = 0.0522);
MVP
0.84
ClinPred
0.32
T
GERP RS
5.4
Varity_R
0.22
gMVP
0.35

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: rs759523877; hg19: chr17-18022329; API