rs2072653

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_016239.4(MYO15A):c.5649+14G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.143 in 1,612,992 control chromosomes in the GnomAD database, including 21,468 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.16 ( 2475 hom., cov: 33)

Exomes 𝑓: 0.14 ( 18993 hom. )

Consequence

MYO15A
NM_016239.4 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -0.909

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.76).

BP6

Variant 17-18141784-G-A is Benign according to our data. Variant chr17-18141784-G-A is described in ClinVar as [Benign]. Clinvar id is 45750.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-18141784-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.487 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYO15A	NM_016239.4 linkuse as main transcript	c.5649+14G>A		intron_variant		ENST00000647165.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYO15A	ENST00000647165.2 linkuse as main transcript	c.5649+14G>A		intron_variant			NM_016239.4	P1	Q9UKN7-1
MYO15A	ENST00000412324.1 linkuse as main transcript	n.660+14G>A		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes

AF:

0.159

AC:

24107

AN:

152060

Hom.:

2468

Cov.:

show subpopulations

Gnomad AFR

AF:

0.148

Gnomad AMI

AF:

0.0768

Gnomad AMR

AF:

0.261

Gnomad ASJ

AF:

0.112

Gnomad EAS

AF:

0.503

Gnomad SAS

AF:

0.163

Gnomad FIN

AF:

0.180

Gnomad MID

AF:

0.0854

Gnomad NFE

AF:

0.116

Gnomad OTH

AF:

0.155

GnomAD3 exomes

AF:

0.186

AC:

46397

AN:

249124

Hom.:

6374

AF XY:

0.175

AC XY:

23655

AN XY:

135220

show subpopulations

Gnomad AFR exome

AF:

0.150

Gnomad AMR exome

AF:

0.358

Gnomad ASJ exome

AF:

0.113

Gnomad EAS exome

AF:

0.503

Gnomad SAS exome

AF:

0.151

Gnomad FIN exome

AF:

0.171

Gnomad NFE exome

AF:

0.109

Gnomad OTH exome

AF:

0.155

GnomAD4 exome

AF:

0.141

AC:

206290

AN:

1460814

Hom.:

18993

Cov.:

AF XY:

0.140

AC XY:

102074

AN XY:

726754

show subpopulations

Gnomad4 AFR exome

AF:

0.144

Gnomad4 AMR exome

AF:

0.344

Gnomad4 ASJ exome

AF:

0.115

Gnomad4 EAS exome

AF:

0.492

Gnomad4 SAS exome

AF:

0.153

Gnomad4 FIN exome

AF:

0.173

Gnomad4 NFE exome

AF:

0.118

Gnomad4 OTH exome

AF:

0.157

GnomAD4 genome

AF:

0.159

AC:

24124

AN:

152178

Hom.:

2475

Cov.:

AF XY:

0.167

AC XY:

12430

AN XY:

74388

show subpopulations

Gnomad4 AFR

AF:

0.148

Gnomad4 AMR

AF:

0.263

Gnomad4 ASJ

AF:

0.112

Gnomad4 EAS

AF:

0.503

Gnomad4 SAS

AF:

0.161

Gnomad4 FIN

AF:

0.180

Gnomad4 NFE

AF:

0.116

Gnomad4 OTH

AF:

0.158

Alfa

AF:

0.120

Hom.:

1485

Bravo

AF:

0.167

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 29, 2018	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 07, 2012	5649+14G>A in Intron 23 of MYO15A: This variant is not expected to have clinical significance because it is not located within the conserved splice consensus se quence and has been identified in 13.8% (479/3462) of African American chromosom es from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs. washington.edu/EVS; dbSNP rs2072653). -

Autosomal recessive nonsyndromic hearing loss 3

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.76

CADD

Benign

7.0

DANN

Benign

0.82

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.

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