rs397517285

Positions:

• chr17-18148784-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PM5 PP3_Moderate PP5_Moderate

The NM_016239.4(MYO15A):​c.6788G>A​(p.Gly2263Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G2263S) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: MYO15A NM_016239.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.77

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-18148783-G-A is described in Lovd as [Likely_pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.931
• PP5: Variant 17-18148784-G-A is Pathogenic according to our data. Variant chr17-18148784-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 45756.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYO15A	NM_016239.4	c.6788G>A	p.Gly2263Asp	missense_variant	33/66	ENST00000647165.2	NP_057323.3
MYO15A	XM_017024715.3	c.6791G>A	p.Gly2264Asp	missense_variant	31/64		XP_016880204.1
MYO15A	XM_017024714.3	c.6728G>A	p.Gly2243Asp	missense_variant	30/63		XP_016880203.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYO15A	ENST00000647165.2	c.6788G>A	p.Gly2263Asp	missense_variant	33/66		NM_016239.4	ENSP00000495481.1
MYO15A	ENST00000578999.1	n.300G>A		non_coding_transcript_exon_variant	3/4	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1449532 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 720078

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Rare genetic deafness Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 05, 2013

The Gly2263Asp variant in MYO15A has not been reported in the literature nor pre viously identified by our laboratory in any other families. Computational analys es (biochemical amino acid properties, conservation, AlignGVGD, PolyPhen2, and S IFT) suggest that the Gly2263Asp variant may impact the protein, though this inf ormation alone is not sufficient to assume pathogenicity. The variant was found to be in trans with a second pathogenic variant in MYO15A in this family, sugges ting that this variant is more likely to be pathogenic. In summary, this variant is likely to be pathogenic, though additional evidence is required to fully est ablish its clinical significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.44
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.50	D;D;D
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.79	T;.;T
M_CAP	Pathogenic	0.62	D
MetaRNN	Pathogenic	0.93	D;D;D
MetaSVM	Pathogenic	0.94	D
MutationAssessor	Pathogenic	3.2	.;M;M
PrimateAI	Uncertain	0.66	T
PROVEAN	Pathogenic	-6.4	.;D;.
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	.;D;.
Sift4G	Pathogenic	0.0	D;D;.
Polyphen		1.0	.;D;D
Vest4		0.54
MutPred		0.70		Loss of MoRF binding (P = 0.0604);Loss of MoRF binding (P = 0.0604);Loss of MoRF binding (P = 0.0604);
MVP		0.89
ClinPred		1.0	D
GERP RS		4.3
Varity_R		0.87
gMVP		0.98

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

Other links and lift over

dbSNP: rs397517285; hg19: chr17-18052098;