Variant rs876657898 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PM4

The NM_016239.4(MYO15A):c.349_357del(p.Tyr117_Arg119del) variant causes a inframe deletion change. The variant allele was found at a frequency of 0.000855 in 1,611,294 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00060 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00088 ( 1 hom. )

Consequence

MYO15A
NM_016239.4 inframe_deletion

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:6

Conservation

PhyloP100: 5.03

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]

MYO15A links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM4

Nonframeshift variant in NON repetitive region in NM_016239.4.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYO15A	NM_016239.4 linkuse as main transcript	c.349_357del	p.Tyr117_Arg119del	inframe_deletion	2/66	ENST00000647165.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYO15A	ENST00000647165.2 linkuse as main transcript	c.349_357del	p.Tyr117_Arg119del	inframe_deletion	2/66		NM_016239.4	P1	Q9UKN7-1
MYO15A	ENST00000583079.1 linkuse as main transcript			upstream_gene_variant

Frequencies

GnomAD3 genomes

AF:

0.000598

AC:

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000719

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:

0.00112

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000495

AC:

117

AN:

236402

Hom.:

AF XY:

0.000512

AC XY:

AN XY:

130974

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000558

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:

0.000879

Gnomad OTH exome

AF:

0.00104

GnomAD4 exome

AF:

0.000881

AC:

1286

AN:

1458980

Hom.:

AF XY:

0.000880

AC XY:

639

AN XY:

725792

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.000515

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:

0.00107

Gnomad4 OTH exome

AF:

0.00118

GnomAD4 genome

AF:

0.000597

AC:

AN:

152314

Hom.:

Cov.:

AF XY:

0.000591

AC XY:

AN XY:

74472

show subpopulations

Gnomad4 AFR

AF:

0.0000962

Gnomad4 AMR

AF:

0.000718

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00112

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000608

Hom.:

Bravo

AF:

0.000627

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:5

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Apr 19, 2024	In-frame deletion of 3 amino acids in a non-repeat region; In silico analysis supports a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jul 25, 2019	The p.Tyr117_Arg119del variant in MYO15A has been previously reported by our laboratory in 1 individual with hearing loss, and has also been identified in 0.08% (103/120036) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant is a deletion of three amino acids at positions 117 to 119 and is not predicted to alter the protein reading-frame of the gene. It is unclear if this deletion will impact the protein function. In summary, the clinical significance of the p.Tyr117_Arg119del variant is uncertain. ACMG/AMP Criteria applied: BS1_Supporting. -
Uncertain significance, criteria provided, single submitter	clinical testing	Knight Diagnostic Laboratories, Oregon Health and Sciences University	Oct 16, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 12, 2022	This variant, c.349_357del, results in the deletion of 3 amino acid(s) of the MYO15A protein (p.Tyr117_Arg119del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs752352091, gnomAD 0.09%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with MYO15A-related conditions. ClinVar contains an entry for this variant (Variation ID: 228948). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2017	- -

Autosomal recessive nonsyndromic hearing loss 3

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Feb 03, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over