chr17-18148547-C-T

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.6743C>T(p.Ala2248Val) variant causes a missense change. The variant allele was found at a frequency of 0.00133 in 1,552,474 control chromosomes in the GnomAD database, including 31 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00080 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0014 ( 30 hom. )

Consequence

MYO15A
NM_016239.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:3

Conservation

PhyloP100: 4.54

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=0.0093669295).

BP6

Variant 17-18148547-C-T is Benign according to our data. Variant chr17-18148547-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 45755.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000801 (122/152246) while in subpopulation SAS AF = 0.0145 (70/4828). AF 95% confidence interval is 0.0118. There are 1 homozygotes in GnomAd4. There are 76 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 30 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.6743C>T	p.Ala2248Val	missense	Exon 32 of 66	NP_057323.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYO15A	ENST00000647165.2	MANE Select	c.6743C>T	p.Ala2248Val	missense	Exon 32 of 66	ENSP00000495481.1	Q9UKN7-1
	MYO15A	ENST00000578999.1	TSL:5	n.277-214C>T		intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.000802

AC:

122

AN:

152128

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000966

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000458

Gnomad ASJ

AF:

0.00662

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0145

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000235

Gnomad OTH

AF:

0.000957

GnomAD2 exomes

AF:

0.00332

AC:

517

AN:

155910

AF XY:

0.00452

show subpopulations

Gnomad AFR exome

AF:

0.000124

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00621

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000328

Gnomad OTH exome

AF:

0.00137

GnomAD4 exome

AF:

0.00139

AC:

1945

AN:

1400228

Hom.:

Cov.:

AF XY:

0.00196

AC XY:

1353

AN XY:

690720

show subpopulations

African (AFR)

AF:

0.0000632

AC:

AN:

31628

American (AMR)

AF:

0.0000557

AC:

AN:

35914

Ashkenazi Jewish (ASJ)

AF:

0.00731

AC:

184

AN:

25188

East Asian (EAS)

AF:

0.00

AC:

AN:

35786

South Asian (SAS)

AF:

0.0182

AC:

1444

AN:

79284

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49272

Middle Eastern (MID)

AF:

0.00281

AC:

AN:

5698

European-Non Finnish (NFE)

AF:

0.000179

AC:

193

AN:

1079408

Other (OTH)

AF:

0.00179

AC:

104

AN:

58050

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

159

318

476

635

794

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

112

140

<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:

0.000801

AC:

122

AN:

152246

Hom.:

Cov.:

AF XY:

0.00102

AC XY:

AN XY:

74438

show subpopulations

African (AFR)

AF:

0.0000963

AC:

AN:

41550

American (AMR)

AF:

0.000458

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00662

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.0145

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000235

AC:

AN:

67992

Other (OTH)

AF:

0.000947

AC:

AN:

2112

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:

0.000674

Hom.:

Bravo

AF:

0.000514

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000371

AC:

ExAC

AF:

0.00242

AC:

236

Asia WGS

AF:

0.00520

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Autosomal recessive nonsyndromic hearing loss 3 (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.35

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Uncertain

-0.060

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.13

Eigen

Uncertain

0.40

Eigen_PC

Uncertain

0.40

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.88

MetaRNN

Benign

0.0094

MetaSVM

Uncertain

0.52

MutationAssessor

Pathogenic

3.2

PhyloP100

4.5

PrimateAI

Uncertain

0.56

PROVEAN

Uncertain

-3.8

REVEL

Pathogenic

0.66

Sift

Benign

0.043

Sift4G

Uncertain

0.0020

Polyphen

0.91

Vest4

0.38

MVP

0.78

ClinPred

0.095

GERP RS

4.3

Varity_R

0.39

gMVP

0.77

Mutation Taster

=46/54

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.11

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