17-18120952-T-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_016239.4(MYO15A):c.2152T>G(p.Trp718Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.347 in 1,479,028 control chromosomes in the GnomAD database, including 97,834 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.36 ( 10430 hom., cov: 33)

Exomes 𝑓: 0.35 ( 87404 hom. )

Consequence

MYO15A
NM_016239.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: -0.213

Publications

26 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

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=3.5260234E-6).

BP6

Variant 17-18120952-T-G is Benign according to our data. Variant chr17-18120952-T-G is described in ClinVar as Benign. ClinVar VariationId is 226779.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.686 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.2152T>G	p.Trp718Gly	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.2152T>G	p.Trp718Gly	missense	Exon 2 of 66	ENSP00000495481.1	Q9UKN7-1
	MYO15A	ENST00000583079.1	TSL:6	n.1785T>G		non_coding_transcript_exon	Exon 1 of 1

Frequencies

GnomAD3 genomes

AF:

0.358

AC:

53875

AN:

150502

Hom.:

10419

Cov.:

show subpopulations

Gnomad AFR

AF:

0.302

Gnomad AMI

AF:

0.418

Gnomad AMR

AF:

0.435

Gnomad ASJ

AF:

0.402

Gnomad EAS

AF:

0.636

Gnomad SAS

AF:

0.706

Gnomad FIN

AF:

0.413

Gnomad MID

AF:

0.341

Gnomad NFE

AF:

0.318

Gnomad OTH

AF:

0.361

GnomAD2 exomes

AF:

0.446

AC:

38542

AN:

86400

AF XY:

0.463

show subpopulations

Gnomad AFR exome

AF:

0.278

Gnomad AMR exome

AF:

0.475

Gnomad ASJ exome

AF:

0.398

Gnomad EAS exome

AF:

0.599

Gnomad FIN exome

AF:

0.387

Gnomad NFE exome

AF:

0.300

Gnomad OTH exome

AF:

0.387

GnomAD4 exome

AF:

0.346

AC:

459558

AN:

1328418

Hom.:

87404

Cov.:

AF XY:

0.357

AC XY:

234014

AN XY:

655368

show subpopulations

African (AFR)

AF:

0.302

AC:

8061

AN:

26692

American (AMR)

AF:

0.470

AC:

13703

AN:

29150

Ashkenazi Jewish (ASJ)

AF:

0.407

AC:

9409

AN:

23136

East Asian (EAS)

AF:

0.658

AC:

19174

AN:

29134

South Asian (SAS)

AF:

0.697

AC:

51526

AN:

73888

European-Finnish (FIN)

AF:

0.383

AC:

12945

AN:

33836

Middle Eastern (MID)

AF:

0.394

AC:

1720

AN:

4360

European-Non Finnish (NFE)

AF:

0.306

AC:

322365

AN:

1053210

Other (OTH)

AF:

0.375

AC:

20655

AN:

55012

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

16463

32927

49390

65854

82317

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

10960

21920

32880

43840

54800

<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:

0.358

AC:

53913

AN:

150610

Hom.:

10430

Cov.:

AF XY:

0.370

AC XY:

27258

AN XY:

73620

show subpopulations

African (AFR)

AF:

0.302

AC:

12470

AN:

41278

American (AMR)

AF:

0.436

AC:

6605

AN:

15152

Ashkenazi Jewish (ASJ)

AF:

0.402

AC:

1390

AN:

3460

East Asian (EAS)

AF:

0.637

AC:

3235

AN:

5080

South Asian (SAS)

AF:

0.706

AC:

3399

AN:

4814

European-Finnish (FIN)

AF:

0.413

AC:

4136

AN:

10004

Middle Eastern (MID)

AF:

0.333

AC:

AN:

288

European-Non Finnish (NFE)

AF:

0.318

AC:

21449

AN:

67540

Other (OTH)

AF:

0.361

AC:

753

AN:

2084

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1769

3537

5306

7074

8843

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

530

1060

1590

2120

2650

<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:

0.353

Hom.:

3802

Bravo

AF:

0.351

TwinsUK

AF:

0.304

AC:

1128

ALSPAC

AF:

0.299

AC:

1152

ExAC

AF:

0.276

AC:

9882

Asia WGS

AF:

0.621

AC:

2083

AN:

3358

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (6)

Autosomal recessive nonsyndromic hearing loss 3 (4)

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.11

CADD

Benign

(source)

DANN

Benign

0.70

DEOGEN2

Benign

0.027

Eigen

Benign

-0.33

Eigen_PC

Benign

-0.33

FATHMM_MKL

Benign

0.37

LIST_S2

Benign

0.42

MetaRNN

Benign

0.0000035

MetaSVM

Benign

-0.89

MutationAssessor

Benign

1.8

PhyloP100

-0.21

PrimateAI

Pathogenic

0.87

PROVEAN

Benign

-2.2

REVEL

Uncertain

0.32

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.011

Polyphen

0.81

Vest4

0.46

ClinPred

0.070

GERP RS

3.0

Varity_R

0.39

gMVP

0.22

Mutation Taster

=91/9

polymorphism (auto)

(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

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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