rs727503318

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_016239.4(MYO15A):ā€‹c.8404A>Gā€‹(p.Met2802Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,444 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: not found (cov: 33)
Exomes š‘“: 0.0000027 ( 0 hom. )

Consequence

MYO15A
NM_016239.4 missense

Scores

19

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.409
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 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.06844258).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
MYO15ANM_016239.4 linkuse as main transcriptc.8404A>G p.Met2802Val missense_variant 47/66 ENST00000647165.2 NP_057323.3
LOC105371567XR_001752809.1 linkuse as main transcript upstream_gene_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
MYO15AENST00000647165.2 linkuse as main transcriptc.8404A>G p.Met2802Val missense_variant 47/66 NM_016239.4 ENSP00000495481 P1Q9UKN7-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD3 exomes
AF:
0.00000803
AC:
2
AN:
249122
Hom.:
0
AF XY:
0.00000739
AC XY:
1
AN XY:
135278
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 SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000177
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000274
AC:
4
AN:
1461444
Hom.:
0
Cov.:
34
AF XY:
0.00000550
AC XY:
4
AN XY:
727032
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:
0.00000360
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33
Bravo
AF:
0.00000378
ExAC
AF:
0.00000826
AC:
1

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineMay 21, 2013The Met2802Val variant in MYO15A has not been reported in affected individuals o r in large population studies. Computational analyses (biochemical amino acid pr operties, conservation, AlignGVGD, PolyPhen2, and SIFT) suggest that the variant may not impact the protein, particularly given a lack of amino acid conservatio n at the Met2802 site including a Val residue in another mammal. However, we can not rule out pathogenicity, especially in light of the existing MYO15A variant i dentified. In summary, the clinical significance of this variant cannot be deter mined with certainty. We recommend parental testing to assess cis/trans configur ation with the other MYO15A variant. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.080
BayesDel_addAF
Benign
-0.31
T
BayesDel_noAF
Benign
-0.38
CADD
Benign
17
DANN
Benign
0.94
DEOGEN2
Benign
0.015
T;T;T;.;.
Eigen
Benign
-0.80
Eigen_PC
Benign
-0.69
FATHMM_MKL
Benign
0.32
N
LIST_S2
Benign
0.71
T;.;T;T;T
M_CAP
Benign
0.021
T
MetaRNN
Benign
0.068
T;T;T;T;T
MetaSVM
Benign
-0.86
T
MutationAssessor
Benign
0.65
.;N;N;.;.
MutationTaster
Benign
1.0
N;N;N
PrimateAI
Benign
0.36
T
PROVEAN
Benign
-1.5
.;N;.;.;.
REVEL
Benign
0.13
Sift
Benign
0.40
.;T;.;.;.
Sift4G
Benign
0.43
T;T;.;T;.
Polyphen
0.0010
.;B;B;.;.
Vest4
0.35
MutPred
0.34
Gain of ubiquitination at K2804 (P = 0.0797);Gain of ubiquitination at K2804 (P = 0.0797);Gain of ubiquitination at K2804 (P = 0.0797);.;.;
MVP
0.64
ClinPred
0.036
T
GERP RS
0.56
Varity_R
0.041
gMVP
0.24

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.040
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: rs727503318; hg19: chr17-18058691; API