rs200623501

chr17-18148781-G-A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_016239.4(MYO15A):c.6785G>A(p.Arg2262His) variant causes a missense change. The variant allele was found at a frequency of 0.000284 in 1,601,318 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts 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. R2262C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0015 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00016 (2 hom.)
• Consequence: MYO15A NM_016239.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:3
• Conservation: PhyloP100: 5.42

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 Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.011348724).
• BP6: Variant 17-18148781-G-A is Benign according to our data. Variant chr17-18148781-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 178448.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=3}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYO15A	NM_016239.4	c.6785G>A	p.Arg2262His	missense_variant	33/66	ENST00000647165.2
MYO15A	XM_017024715.3	c.6788G>A	p.Arg2263His	missense_variant	31/64
MYO15A	XM_017024714.3	c.6725G>A	p.Arg2242His	missense_variant	30/63

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYO15A	ENST00000647165.2	c.6785G>A	p.Arg2262His	missense_variant	33/66		NM_016239.4	P1
MYO15A	ENST00000578999.1	n.297G>A		non_coding_transcript_exon_variant	3/4	5

Frequencies

GnomAD3 genomes AF: 0.00149 AC: 226 AN: 152170 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00502

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000785

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.000315 AC: 71 AN: 225674 Hom.: 0 AF XY: 0.000236 AC XY: 29 AN XY: 122910

Gnomad AFR exome AF: 0.00434

Gnomad AMR exome AF: 0.000273

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000357

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000398

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000157 AC: 228 AN: 1449030 Hom.: 2 Cov.: 34 AF XY: 0.000135 AC XY: 97 AN XY: 719752

Gnomad4 AFR exome AF: 0.00482

Gnomad4 AMR exome AF: 0.000252

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000357

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000317

Gnomad4 OTH exome AF: 0.000301

GnomAD4 genome AF: 0.00148 AC: 226 AN: 152288 Hom.: 0 Cov.: 32 AF XY: 0.00136 AC XY: 101 AN XY: 74468

Gnomad4 AFR AF: 0.00503

Gnomad4 AMR AF: 0.000784

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000875 Hom.: 0

Bravo AF: 0.00181

ESP6500AA AF: 0.00681 AC: 28

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000431 AC: 52

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 20, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 24, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 12, 2020	- -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 25, 2022

The c.6785G>A (p.R2262H) alteration is located in exon 33 (coding exon 32) of the MYO15A gene. This alteration results from a G to A substitution at nucleotide position 6785, causing the arginine (R) at amino acid position 2262 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Oct 05, 2017

p.Arg2262His in exon 33 of MYO15A: This variant is not expected to have clinical significance because it has been identified in 0.46% (100/21764) of African chr omosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitut e.org; dbSNP rs200623501). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.14
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Benign	0.036	T;T;T
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.86	D;.;D
M_CAP	Pathogenic	0.30	D
MetaRNN	Benign	0.011	T;T;T
MetaSVM	Uncertain	0.26	D
MutationTaster	Benign	0.85	D
PrimateAI	Benign	0.47	T
Sift4G	Pathogenic	0.0010	D;D;.
Polyphen		0.96	.;D;D
Vest4		0.40
MVP		0.79
ClinPred		0.088	T
GERP RS		4.3
Varity_R		0.14
gMVP		0.85

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs200623501; hg19: chr17-18052095;