rs139347804

chr17-18142824-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_016239.4(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. 13/19 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 Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0043 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0058 (33 hom.)
• Consequence: MYO15A NM_016239.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 2.32

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]

ACMG classification

Verdict is Benign. Variant got -9 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 id is 178445.We mark this variant Likely_benign, oryginal submissions are: {Benign=3, Uncertain_significance=1, Likely_benign=1}. Variant chr17-18142824-G-A is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYO15A	NM_016239.4	c.5894G>A	p.Arg1965His	missense_variant	25/66	ENST00000647165.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYO15A	ENST00000647165.2	c.5894G>A	p.Arg1965His	missense_variant	25/66		NM_016239.4	P1

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

GnomAD3 exomes AF: 0.00441 AC: 1077 AN: 244424 Hom.: 2 AF XY: 0.00424 AC XY: 563 AN XY: 132912

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 SAS exome AF: 0.000498

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

Gnomad4 AFR exome AF: 0.00102

Gnomad4 AMR exome AF: 0.00130

Gnomad4 ASJ exome AF: 0.00127

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000803

Gnomad4 FIN exome AF: 0.00866

Gnomad4 NFE exome AF: 0.00678

Gnomad4 OTH exome AF: 0.00482

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

Gnomad4 AFR AF: 0.00123

Gnomad4 AMR AF: 0.00131

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00762

Gnomad4 NFE AF: 0.00725

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00576 Hom.: 7

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

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	MYO15A: BP4, BS1 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 29, 2019	- -

Autosomal recessive nonsyndromic hearing loss 3 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 30, 2012

Arg1965His in Exon 25 of MYO15A: This variant is not expected to have clinical s ignificance because it has been identified in 0.6% (43/6736) of European America n chromosomes from a broad population by the NHLBI Exome Sequencing Project (htt p://evs.gs.washington.edu/EVS; dbSNP rs139347804). -

Computational scores

Source: dbNSFP v4.3

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;D;D
Eigen	Benign	-0.69
Eigen_PC	Benign	-0.57
FATHMM_MKL	Benign	0.72	D
LIST_S2	Benign	0.73	T;.;T
MetaRNN	Benign	0.0084	T;T;T
MetaSVM	Benign	-0.56	T
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.20	T
Sift4G	Benign	0.42	T;T;.
Polyphen		0.010	.;B;B
Vest4		0.30
MVP		0.60
ClinPred		0.032	T
GERP RS		0.56
Varity_R		0.059
gMVP		0.57

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

Publications

LitVar

Other links and lift over

dbSNP: rs139347804; hg19: chr17-18046138;