17-18148176-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_016239.4(MYO15A):​c.6657G>C​(p.Lys2219Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,468 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 (★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

MYO15A
NM_016239.4 missense

Scores

1
12
6

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.467
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.34776223).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
MYO15ANM_016239.4 linkc.6657G>C p.Lys2219Asn missense_variant Exon 31 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.6657G>C p.Lys2219Asn missense_variant Exon 31 of 66 NM_016239.4 ENSP00000495481.1 Q9UKN7-1
MYO15AENST00000578999.1 linkn.242G>C non_coding_transcript_exon_variant Exon 2 of 4 5

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.00000205
AC:
3
AN:
1461468
Hom.:
0
Cov.:
32
AF XY:
0.00000275
AC XY:
2
AN XY:
727044
show subpopulations
Gnomad4 AFR exome
AF:
0.00
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:
0.00000270
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Uncertain:1
May 25, 2022
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces lysine, which is basic and polar, with asparagine, which is neutral and polar, at codon 2219 of the MYO15A protein (p.Lys2219Asn). 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. 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. This variant has not been reported in the literature in individuals affected with MYO15A-related conditions. This variant is not present in population databases (gnomAD no frequency). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.46
BayesDel_addAF
Benign
-0.058
T
BayesDel_noAF
Benign
-0.32
CADD
Benign
21
DANN
Uncertain
1.0
DEOGEN2
Benign
0.17
T;D;D
Eigen
Uncertain
0.42
Eigen_PC
Uncertain
0.34
FATHMM_MKL
Uncertain
0.81
D
LIST_S2
Benign
0.75
T;.;T
M_CAP
Uncertain
0.22
D
MetaRNN
Benign
0.35
T;T;T
MetaSVM
Uncertain
0.49
D
MutationAssessor
Uncertain
2.8
.;M;M
PrimateAI
Uncertain
0.51
T
PROVEAN
Uncertain
-3.4
.;D;.
REVEL
Uncertain
0.49
Sift
Uncertain
0.0020
.;D;.
Sift4G
Pathogenic
0.0010
D;D;.
Polyphen
0.99
.;D;D
Vest4
0.53
MutPred
0.45
Loss of ubiquitination at K2219 (P = 0.0148);Loss of ubiquitination at K2219 (P = 0.0148);Loss of ubiquitination at K2219 (P = 0.0148);
MVP
0.83
ClinPred
0.93
D
GERP RS
3.1
Varity_R
0.34
gMVP
0.89

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: rs727504708; hg19: chr17-18051490; API