chr17-18142824-G-A

Variant names:

• chr17-18142824-G-A
• rs139347804
• NM_016239.4:c.5894G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The ENST00000647165.2(MYO15A):​c.5894G>A​(p.Arg1965His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00567 in 1,612,588 control chromosomes in the GnomAD database, including 35 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 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. R1965C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0043 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0058 (33 hom.)
• Consequence: MYO15A ENST00000647165.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 2.32
• Publications: 6 publications found

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), PanelApp Australia
• nonsyndromic genetic hearing loss

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.008371383).
• BP6: Variant 17-18142824-G-A is Benign according to our data. Variant chr17-18142824-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 178445.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00432 (658/152282) while in subpopulation NFE AF = 0.00725 (493/68014). AF 95% confidence interval is 0.00672. There are 2 homozygotes in GnomAd4. There are 323 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: ENST00000647165.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYO15A	NM_016239.4	MANE Select	c.5894G>A	p.Arg1965His	missense	Exon 25 of 66	NP_057323.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYO15A	ENST00000647165.2	MANE Select	c.5894G>A	p.Arg1965His	missense	Exon 25 of 66	ENSP00000495481.1

Frequencies

GnomAD3 genomes AF: 0.00432 AC: 658 AN: 152164 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00123

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00762

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00725

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00441 AC: 1077 AN: 244424 AF XY: 0.00424

Gnomad AFR exome AF: 0.00114

Gnomad AMR exome AF: 0.00123

Gnomad ASJ exome AF: 0.00192

Gnomad EAS exome AF: 0.0000561

Gnomad FIN exome AF: 0.00871

Gnomad NFE exome AF: 0.00694

Gnomad OTH exome AF: 0.00562

GnomAD4 exome AF: 0.00582 AC: 8493 AN: 1460306 Hom.: 33 Cov.: 34 AF XY: 0.00575 AC XY: 4177 AN XY: 726330

African (AFR) AF: 0.00102 AC: 34 AN: 33442

American (AMR) AF: 0.00130 AC: 58 AN: 44598

Ashkenazi Jewish (ASJ) AF: 0.00127 AC: 33 AN: 26040

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39664

South Asian (SAS) AF: 0.000803 AC: 69 AN: 85910

European-Finnish (FIN) AF: 0.00866 AC: 460 AN: 53122

Middle Eastern (MID) AF: 0.00139 AC: 8 AN: 5764

European-Non Finnish (NFE) AF: 0.00678 AC: 7539 AN: 1111430

Other (OTH) AF: 0.00482 AC: 291 AN: 60336

GnomAD4 genome AF: 0.00432 AC: 658 AN: 152282 Hom.: 2 Cov.: 32 AF XY: 0.00434 AC XY: 323 AN XY: 74466

African (AFR) AF: 0.00123 AC: 51 AN: 41550

American (AMR) AF: 0.00131 AC: 20 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4832

European-Finnish (FIN) AF: 0.00762 AC: 81 AN: 10624

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00725 AC: 493 AN: 68014

Other (OTH) AF: 0.00237 AC: 5 AN: 2114

Alfa AF: 0.00554 Hom.: 8

Bravo AF: 0.00358

TwinsUK AF: 0.00458 AC: 17

ALSPAC AF: 0.00727 AC: 28

ESP6500AA AF: 0.00100 AC: 4

ESP6500EA AF: 0.00756 AC: 63

ExAC AF: 0.00430 AC: 520

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.00573

EpiControl AF: 0.00536

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	1	-	Autosomal recessive nonsyndromic hearing loss 3 (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.34	T
Eigen	Benign	-0.69
Eigen_PC	Benign	-0.57
FATHMM_MKL	Benign	0.72	D
LIST_S2	Benign	0.73	T
MetaRNN	Benign	0.0084	T
MetaSVM	Benign	-0.56	T
MutationAssessor	Benign	0.74	N
PhyloP100		2.3
PrimateAI	Benign	0.20	T
PROVEAN	Uncertain	-3.1	D
REVEL	Benign	0.26
Sift	Benign	0.15	T
Sift4G	Benign	0.42	T
Polyphen		0.010	B
Vest4		0.30
MVP		0.60
ClinPred		0.032	T
GERP RS		0.56
Varity_R		0.059
gMVP		0.57
Mutation Taster		=79/21	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs139347804; hg19: chr17-18046138;