rs376470294

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4BP6

The NM_016239.4(MYO15A):ā€‹c.9982A>Cā€‹(p.Ser3328Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000811 in 1,603,626 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: š‘“ 0.000066 ( 0 hom., cov: 34)
Exomes š‘“: 0.0000021 ( 0 hom. )

Consequence

MYO15A
NM_016239.4 missense

Scores

9
10

Clinical Significance

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

Conservation

PhyloP100: 4.33
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=0.34162128).
BP6
Variant 17-18167623-A-C is Benign according to our data. Variant chr17-18167623-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 178451.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
MYO15ANM_016239.4 linkuse as main transcriptc.9982A>C p.Ser3328Arg missense_variant 62/66 ENST00000647165.2 NP_057323.3 Q9UKN7-1
MYO15AXM_017024715.3 linkuse as main transcriptc.9985A>C p.Ser3329Arg missense_variant 60/64 XP_016880204.1
MYO15AXM_017024714.3 linkuse as main transcriptc.9922A>C p.Ser3308Arg missense_variant 59/63 XP_016880203.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
MYO15AENST00000647165.2 linkuse as main transcriptc.9982A>C p.Ser3328Arg missense_variant 62/66 NM_016239.4 ENSP00000495481.1 Q9UKN7-1

Frequencies

GnomAD3 genomes
AF:
0.0000657
AC:
10
AN:
152258
Hom.:
0
Cov.:
34
show subpopulations
Gnomad AFR
AF:
0.000241
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:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000125
AC:
3
AN:
240378
Hom.:
0
AF XY:
0.00000760
AC XY:
1
AN XY:
131602
show subpopulations
Gnomad AFR exome
AF:
0.000197
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:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000207
AC:
3
AN:
1451368
Hom.:
0
Cov.:
32
AF XY:
0.00000277
AC XY:
2
AN XY:
722452
show subpopulations
Gnomad4 AFR exome
AF:
0.0000896
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:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000657
AC:
10
AN:
152258
Hom.:
0
Cov.:
34
AF XY:
0.0000672
AC XY:
5
AN XY:
74392
show subpopulations
Gnomad4 AFR
AF:
0.000241
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000604
ESP6500AA
AF:
0.000488
AC:
2
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.0000248
AC:
3

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineOct 11, 2013The Ser3328Arg variant in MYO15A has not been previously reported in individuals with hearing loss, but has been identified in 0.04% (2/4102) of African America n chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.ed u/EVS/; dbSNP rs376470294). Computational analyses (biochemical amino acid prope rties, conservation, AlignGVGD, PolyPhen2, and SIFT) do not provide strong suppo rt for or against an impact to the protein. In summary, additional data is neede d to determine the clinical significance of this variant. -
not provided Benign:1
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpAug 07, 2023- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.38
BayesDel_addAF
Benign
-0.13
T
BayesDel_noAF
Benign
-0.14
CADD
Benign
22
DANN
Benign
0.96
DEOGEN2
Benign
0.020
T;T;T;.;.
Eigen
Uncertain
0.30
Eigen_PC
Uncertain
0.36
FATHMM_MKL
Uncertain
0.86
D
LIST_S2
Benign
0.75
T;.;T;T;T
M_CAP
Uncertain
0.21
D
MetaRNN
Benign
0.34
T;T;T;T;T
MetaSVM
Uncertain
0.19
D
MutationAssessor
Benign
1.4
.;L;L;.;.
PrimateAI
Uncertain
0.50
T
PROVEAN
Benign
-1.5
.;N;.;.;.
REVEL
Uncertain
0.48
Sift
Benign
0.51
.;T;.;.;.
Sift4G
Uncertain
0.022
D;D;.;D;.
Polyphen
1.0
.;D;D;.;.
Vest4
0.50
MutPred
0.51
Gain of loop (P = 0.0097);Gain of loop (P = 0.0097);Gain of loop (P = 0.0097);.;.;
MVP
0.78
ClinPred
0.20
T
GERP RS
5.8
Varity_R
0.32
gMVP
0.44

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: rs376470294; hg19: chr17-18070937; API