chr17-18163251-G-A

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM5PP5BP4

The NM_016239.4(MYO15A):c.9620G>A(p.Arg3207His) variant causes a missense change. The variant allele was found at a frequency of 0.0000551 in 1,614,138 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R3207L) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.00026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000034 ( 0 hom. )

Consequence

MYO15A
NM_016239.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:6U:1

Conservation

PhyloP100: 6.47

Publications

7 publications found

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 Gene-Disease associations (from GenCC):

autosomal recessive nonsyndromic hearing loss 3
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), PanelApp Australia
nonsyndromic genetic hearing loss
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
hearing loss, autosomal recessive
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

MYO15A links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr17-18163251-G-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1064985.Status of the report is criteria_provided_single_submitter, 1 stars.

PP5

Variant 17-18163251-G-A is Pathogenic according to our data. Variant chr17-18163251-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 228973.

BP4

Computational evidence support a benign effect (MetaRNN=0.08375016). . Strength limited to SUPPORTING due to the PP5.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016239.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYO15A	NM_016239.4	MANE Select	c.9620G>A	p.Arg3207His	missense	Exon 59 of 66	NP_057323.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
MYO15A	ENST00000647165.2	MANE Select	c.9620G>A	p.Arg3207His	missense	Exon 59 of 66	ENSP00000495481.1
MYO15A	ENST00000433411.7	TSL:1	n.1070G>A		non_coding_transcript_exon	Exon 6 of 13
MYO15A	ENST00000473013.1	TSL:1	n.804G>A		non_coding_transcript_exon	Exon 3 of 4

Frequencies

GnomAD3 genomes

AF:

0.000263

AC:

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00242

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000441

AC:

AN:

249574

AF XY:

0.0000443

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000111

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000177

Gnomad OTH exome

AF:

0.000495

GnomAD4 exome

AF:

0.0000335

AC:

AN:

1461824

Hom.:

Cov.:

AF XY:

0.0000248

AC XY:

AN XY:

727224

show subpopulations

African (AFR)

AF:

0.0000597

AC:

AN:

33476

American (AMR)

AF:

0.000291

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53412

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0000198

AC:

AN:

1111960

Other (OTH)

AF:

0.000166

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.455

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000263

AC:

AN:

152314

Hom.:

Cov.:

AF XY:

0.000242

AC XY:

AN XY:

74478

show subpopulations

African (AFR)

AF:

0.0000481

AC:

AN:

41564

American (AMR)

AF:

0.00242

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68036

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000149

Hom.:

Bravo

AF:

0.000672

ExAC

AF:

0.0000579

AC:

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Autosomal recessive nonsyndromic hearing loss 3 (3)

not provided (2)

MYO15A-related disorder (1)

Rare genetic deafness (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.49

BayesDel_addAF

Uncertain

0.11

BayesDel_noAF

Pathogenic

0.14

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.090

Eigen

Uncertain

0.67

Eigen_PC

Uncertain

0.64

FATHMM_MKL

Uncertain

0.86

LIST_S2

Uncertain

0.96

M_CAP

Pathogenic

0.37

MetaRNN

Benign

0.084

MetaSVM

Pathogenic

0.88

MutationAssessor

Benign

1.8

PhyloP100

6.5

PrimateAI

Uncertain

0.75

PROVEAN

Pathogenic

-4.5

REVEL

Uncertain

0.60

Sift

Benign

0.042

Sift4G

Pathogenic

0.0010

Polyphen

0.94

Vest4

0.49

MVP

0.92

ClinPred

0.89

GERP RS

5.3

Varity_R

0.25

gMVP

0.52

Mutation Taster

=8/92

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over