rs121908970

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 2P and 13B. PM1BP4_StrongBP6BS1BS2

The NM_016239.4(MYO15A):c.6614C>T(p.Thr2205Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00441 in 1,613,862 control chromosomes in the GnomAD database, including 28 homozygotes. In-silico tool predicts 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 0.0040 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0044 ( 26 hom. )

Consequence

MYO15A
NM_016239.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1B:6

Conservation

PhyloP100: 4.57

Publications

25 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 -11 ACMG points.

PM1

In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 3 uncertain in NM_016239.4

BP4

Computational evidence support a benign effect (MetaRNN=0.011911124).

BP6

Variant 17-18148133-C-T is Benign according to our data. Variant chr17-18148133-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 6956.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.004 (609/152352) while in subpopulation NFE AF = 0.00481 (327/68032). AF 95% confidence interval is 0.00438. There are 2 homozygotes in GnomAd4. There are 322 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

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.6614C>T	p.Thr2205Ile	missense	Exon 31 of 66	NP_057323.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYO15A	ENST00000647165.2	MANE Select	c.6614C>T	p.Thr2205Ile	missense	Exon 31 of 66	ENSP00000495481.1	Q9UKN7-1
	MYO15A	ENST00000578999.1	TSL:5	n.199C>T		non_coding_transcript_exon	Exon 2 of 4

Frequencies

GnomAD3 genomes

AF:

0.00400

AC:

609

AN:

152234

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000699

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00124

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00186

Gnomad FIN

AF:

0.0203

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00481

Gnomad OTH

AF:

0.00430

GnomAD2 exomes

AF:

0.00430

AC:

1072

AN:

249018

AF XY:

0.00429

show subpopulations

Gnomad AFR exome

AF:

0.000194

Gnomad AMR exome

AF:

0.00101

Gnomad ASJ exome

AF:

0.000199

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0194

Gnomad NFE exome

AF:

0.00471

Gnomad OTH exome

AF:

0.00462

GnomAD4 exome

AF:

0.00445

AC:

6503

AN:

1461510

Hom.:

Cov.:

AF XY:

0.00439

AC XY:

3189

AN XY:

727064

show subpopulations

African (AFR)

AF:

0.000418

AC:

AN:

33480

American (AMR)

AF:

0.00123

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0000765

AC:

AN:

26130

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00181

AC:

156

AN:

86250

European-Finnish (FIN)

AF:

0.0178

AC:

947

AN:

53070

Middle Eastern (MID)

AF:

0.00104

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00455

AC:

5061

AN:

1111998

Other (OTH)

AF:

0.00434

AC:

262

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

439

877

1316

1754

2193

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

196

392

588

784

980

<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:

0.00400

AC:

609

AN:

152352

Hom.:

Cov.:

AF XY:

0.00432

AC XY:

322

AN XY:

74496

show subpopulations

African (AFR)

AF:

0.000697

AC:

AN:

41592

American (AMR)

AF:

0.00124

AC:

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00186

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.0203

AC:

216

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00481

AC:

327

AN:

68032

Other (OTH)

AF:

0.00426

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

119

149

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:

0.00345

Hom.:

Bravo

AF:

0.00244

TwinsUK

AF:

0.00431

AC:

ALSPAC

AF:

0.00571

AC:

ESP6500AA

AF:

0.000494

AC:

ESP6500EA

AF:

0.00395

AC:

ExAC

AF:

0.00417

AC:

504

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00409

EpiControl

AF:

0.00480

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

not specified (2)

Deafness, with smith-magenis syndrome (1)

Nonsyndromic genetic hearing loss (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.050

BayesDel_noAF

Pathogenic

0.16

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.11

Eigen

Uncertain

0.54

Eigen_PC

Uncertain

0.44

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.64

MetaRNN

Benign

0.012

MetaSVM

Uncertain

0.74

MutationAssessor

Pathogenic

2.9

PhyloP100

4.6

PrimateAI

Uncertain

0.64

PROVEAN

Uncertain

-4.3

REVEL

Pathogenic

0.80

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.0020

Polyphen

0.99

Vest4

0.54

MVP

0.89

ClinPred

0.045

GERP RS

3.1

Varity_R

0.29

gMVP

0.44

Mutation Taster

=32/68

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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