rs150403702

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_016239.4(MYO15A):c.5754T>G(p.Ile1918Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00219 in 1,613,798 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict 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. I1918V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0019 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0022 ( 12 hom. )

Consequence

MYO15A
NM_016239.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:6

Conservation

PhyloP100: 1.01

Publications

4 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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.011315256).

BP6

Variant 17-18142183-T-G is Benign according to our data. Variant chr17-18142183-T-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 178444.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00192 (293/152336) while in subpopulation NFE AF = 0.00337 (229/68032). AF 95% confidence interval is 0.00301. There are 1 homozygotes in GnomAd4. There are 112 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 12 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.5754T>G	p.Ile1918Met	missense	Exon 24 of 66	NP_057323.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYO15A	ENST00000647165.2	MANE Select	c.5754T>G	p.Ile1918Met	missense	Exon 24 of 66	ENSP00000495481.1	Q9UKN7-1
	MYO15A	ENST00000412324.1	TSL:5	n.*46T>G		downstream_gene	N/A

Frequencies

GnomAD3 genomes

AF:

0.00192

AC:

293

AN:

152218

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000458

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000785

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00254

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00337

Gnomad OTH

AF:

0.00143

GnomAD2 exomes

AF:

0.00192

AC:

478

AN:

249312

AF XY:

0.00190

show subpopulations

Gnomad AFR exome

AF:

0.000194

Gnomad AMR exome

AF:

0.00119

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00334

Gnomad NFE exome

AF:

0.00288

Gnomad OTH exome

AF:

0.000990

GnomAD4 exome

AF:

0.00221

AC:

3236

AN:

1461462

Hom.:

Cov.:

AF XY:

0.00229

AC XY:

1663

AN XY:

727026

show subpopulations

African (AFR)

AF:

0.000329

AC:

AN:

33476

American (AMR)

AF:

0.00125

AC:

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.0000765

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00126

AC:

109

AN:

86244

European-Finnish (FIN)

AF:

0.00315

AC:

167

AN:

53068

Middle Eastern (MID)

AF:

0.000348

AC:

AN:

5750

European-Non Finnish (NFE)

AF:

0.00250

AC:

2778

AN:

1111992

Other (OTH)

AF:

0.00184

AC:

111

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

195

390

586

781

976

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

168

252

336

420

<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:

0.00192

AC:

293

AN:

152336

Hom.:

Cov.:

AF XY:

0.00150

AC XY:

112

AN XY:

74500

show subpopulations

African (AFR)

AF:

0.000457

AC:

AN:

41568

American (AMR)

AF:

0.000784

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.000414

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00254

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00337

AC:

229

AN:

68032

Other (OTH)

AF:

0.00142

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

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:

0.00278

Hom.:

Bravo

AF:

0.00180

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.00208

AC:

ESP6500AA

AF:

0.000458

AC:

ESP6500EA

AF:

0.00268

AC:

ExAC

AF:

0.00195

AC:

237

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.00218

EpiControl

AF:

0.00184

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

Autosomal recessive nonsyndromic hearing loss 3 (1)

Inborn genetic diseases (1)

MYO15A-related disorder (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.10

CADD

Benign

(source)

DANN

Benign

0.93

DEOGEN2

Benign

0.019

Eigen

Benign

-0.42

Eigen_PC

Benign

-0.40

FATHMM_MKL

Benign

0.66

LIST_S2

Benign

0.68

M_CAP

Uncertain

0.23

MetaRNN

Benign

0.011

MetaSVM

Uncertain

-0.095

MutationAssessor

Benign

0.97

PhyloP100

1.0

PrimateAI

Benign

0.41

PROVEAN

Benign

-1.4

REVEL

Uncertain

0.45

Sift

Benign

0.057

Sift4G

Uncertain

0.0060

Polyphen

0.88

Vest4

0.54

MVP

0.77

ClinPred

0.031

GERP RS

1.3

Varity_R

0.088

gMVP

0.27

Mutation Taster

=70/30

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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