rs1001523088

Positions:

• chr17-18148889-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM2 PP5_Moderate BP4

The NM_016239.4(MYO15A):​c.6893G>A​(p.Arg2298Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000687 in 1,455,306 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 Likely pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000069 (0 hom.)
• Consequence: MYO15A NM_016239.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 5.22

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-18148889-G-A is Pathogenic according to our data. Variant chr17-18148889-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 517648.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.24490309). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYO15A	NM_016239.4	c.6893G>A	p.Arg2298Gln	missense_variant	33/66	ENST00000647165.2	NP_057323.3
MYO15A	XM_017024715.3	c.6896G>A	p.Arg2299Gln	missense_variant	31/64		XP_016880204.1
MYO15A	XM_017024714.3	c.6833G>A	p.Arg2278Gln	missense_variant	30/63		XP_016880203.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYO15A	ENST00000647165.2	c.6893G>A	p.Arg2298Gln	missense_variant	33/66		NM_016239.4	ENSP00000495481	P1
MYO15A	ENST00000578999.1	n.405G>A		non_coding_transcript_exon_variant	3/4	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000852 AC: 2 AN: 234652 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 127776

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000600

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: 0.00000687 AC: 10 AN: 1455306 Hom.: 0 Cov.: 34 AF XY: 0.00000691 AC XY: 5 AN XY: 723282

Gnomad4 AFR exome AF: 0.0000300

Gnomad4 AMR exome AF: 0.0000455

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000506

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000361

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Nonsyndromic genetic hearing loss Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Feb 02, 2023

The p.Arg2298Gln variant in MYO15A has been previously reported in the homozygous state in two individuals with profound sensorineural hearing loss, and segregated in 9 affected family members from two families (Sloan-Heggen 2015 PMID 26969326, personal communication with authors, Abu Rayyan 2020 PMID 32747562). In addition, the variant was identified by our laboratory in an individual with hearing loss who was compound heterozygous for p.Arg2298Gln and a likely pathogenic MYO15A variant. It has also been identified in 0.005996% (2/33356) of Latino/Admixed American chromosomes by gnomAD (http://gnomad.broadinstitute.org). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal recessive nonsyndromic hearing loss. ACMG/AMP Criteria applied: PP1_Strong, PM2_Supporting, PM3. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Uncertain	0.019	T
BayesDel_noAF	Benign	-0.21
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.030	T;T;T
Eigen	Benign	0.0079
Eigen_PC	Benign	0.10
FATHMM_MKL	Benign	0.74	D
LIST_S2	Uncertain	0.92	D;.;D
M_CAP	Uncertain	0.19	D
MetaRNN	Benign	0.24	T;T;T
MetaSVM	Benign	-0.31	T
MutationAssessor	Uncertain	2.6	.;M;M
MutationTaster	Benign	0.57	N
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-1.5	.;N;.
REVEL	Benign	0.28
Sift	Uncertain	0.017	.;D;.
Sift4G	Uncertain	0.0030	D;D;.
Polyphen		0.29	.;B;B
Vest4		0.24
MutPred		0.39		Loss of sheet (P = 0.0315);Loss of sheet (P = 0.0315);Loss of sheet (P = 0.0315);
MVP		0.78
ClinPred		0.65	D
GERP RS		4.0
Varity_R		0.12
gMVP		0.65

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: rs1001523088; hg19: chr17-18052203;