chr17-18121262-A-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BA1

The NM_016239.4(MYO15A):c.2462A>C(p.Gln821Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00586 in 1,451,342 control chromosomes in the GnomAD database, including 178 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). The gene MYO15A is included in the ClinGen Criteria Specification Registry.

Frequency

Genomes: 𝑓 0.020 ( 76 hom., cov: 32)

Exomes 𝑓: 0.0043 ( 102 hom. )

Consequence

MYO15A
NM_016239.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.0760

Publications

2 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)
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

Specifications for MYO15A are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0025024116).

BP6

Variant 17-18121262-A-C is Benign according to our data. Variant chr17-18121262-A-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 226781.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0565 is higher than 0.05.

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.2462A>C	p.Gln821Pro	missense	Exon 2 of 66	NP_057323.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYO15A	ENST00000647165.2	MANE Select	c.2462A>C	p.Gln821Pro	missense	Exon 2 of 66	ENSP00000495481.1	Q9UKN7-1
	MYO15A	ENST00000583079.1	TSL:6	n.2095A>C		non_coding_transcript_exon	Exon 1 of 1

Frequencies

GnomAD3 genomes

AF:

0.0196

AC:

2947

AN:

150706

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0583

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0121

Gnomad ASJ

AF:

0.0121

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00415

Gnomad FIN

AF:

0.00197

Gnomad MID

AF:

0.0417

Gnomad NFE

AF:

0.00342

Gnomad OTH

AF:

0.0179

GnomAD2 exomes

AF:

0.00544

AC:

386

AN:

70928

AF XY:

0.00524

show subpopulations

Gnomad AFR exome

AF:

0.0559

Gnomad AMR exome

AF:

0.00472

Gnomad ASJ exome

AF:

0.0117

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00125

Gnomad NFE exome

AF:

0.00391

Gnomad OTH exome

AF:

0.0148

GnomAD4 exome

AF:

0.00426

AC:

5541

AN:

1300528

Hom.:

102

Cov.:

AF XY:

0.00416

AC XY:

2669

AN XY:

641502

show subpopulations

African (AFR)

AF:

0.0741

AC:

1895

AN:

25574

American (AMR)

AF:

0.00589

AC:

152

AN:

25826

Ashkenazi Jewish (ASJ)

AF:

0.0113

AC:

243

AN:

21594

East Asian (EAS)

AF:

0.00

AC:

AN:

26928

South Asian (SAS)

AF:

0.00430

AC:

310

AN:

72126

European-Finnish (FIN)

AF:

0.000976

AC:

AN:

32784

Middle Eastern (MID)

AF:

0.0362

AC:

139

AN:

3842

European-Non Finnish (NFE)

AF:

0.00221

AC:

2299

AN:

1038678

Other (OTH)

AF:

0.00886

AC:

471

AN:

53176

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

279

558

838

1117

1396

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

240

360

480

600

<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:

0.0196

AC:

2957

AN:

150814

Hom.:

Cov.:

AF XY:

0.0191

AC XY:

1410

AN XY:

73706

show subpopulations

African (AFR)

AF:

0.0584

AC:

2412

AN:

41288

American (AMR)

AF:

0.0121

AC:

183

AN:

15164

Ashkenazi Jewish (ASJ)

AF:

0.0121

AC:

AN:

3460

East Asian (EAS)

AF:

0.00

AC:

AN:

5120

South Asian (SAS)

AF:

0.00457

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.00197

AC:

AN:

10146

Middle Eastern (MID)

AF:

0.0342

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00342

AC:

231

AN:

67528

Other (OTH)

AF:

0.0177

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

139

279

418

558

697

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

102

136

170

<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:

0.0142

Hom.:

ESP6500AA

AF:

0.0351

AC:

ESP6500EA

AF:

0.00172

AC:

ExAC

AF:

0.00260

AC:

128

Asia WGS

AF:

0.00897

AC:

AN:

3358

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (4)

Autosomal recessive nonsyndromic hearing loss 3 (2)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.058

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.48

CADD

Benign

(source)

DANN

Benign

0.80

DEOGEN2

Benign

0.019

Eigen

Benign

-0.93

Eigen_PC

Benign

-0.82

FATHMM_MKL

Benign

0.13

LIST_S2

Benign

0.42

MetaRNN

Benign

0.0025

MetaSVM

Benign

-0.79

MutationAssessor

Benign

0.0

PhyloP100

-0.076

PrimateAI

Pathogenic

0.85

PROVEAN

Benign

-0.72

REVEL

Benign

0.18

Sift

Uncertain

0.0030

Sift4G

Benign

0.18

Polyphen

0.0

Vest4

0.21

MVP

0.60

ClinPred

0.0081

GERP RS

2.0

Varity_R

0.13

gMVP

0.32

Mutation Taster

=94/6

polymorphism

(source)

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

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