rs146754758

chr17-18124531-G-Achr17-18124531-G-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_016239.4(MYO15A):c.3658G>A(p.Gly1220Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000854 in 1,613,198 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G1220E) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0013 (6 hom., cov: 33)
  • Exomes 𝑓: 0.00081 (13 hom.)
• Consequence: MYO15A NM_016239.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 0.870

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00341475).
• BP6: Variant 17-18124531-G-A is Benign according to our data. Variant chr17-18124531-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 164513.We mark this variant Likely_benign, oryginal submissions are: {Benign=4, Likely_benign=1, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00129 (196/152312) while in subpopulation EAS AF= 0.0339 (176/5190). AF 95% confidence interval is 0.0298. There are 6 homozygotes in gnomad4. There are 122 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYO15A	NM_016239.4	c.3658G>A	p.Gly1220Arg	missense_variant	3/66	ENST00000647165.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYO15A	ENST00000647165.2	c.3658G>A	p.Gly1220Arg	missense_variant	3/66		NM_016239.4	P1
MYO15A	ENST00000651088.1	c.199G>A	p.Gly67Arg	missense_variant	2/2
MYO15A	ENST00000583079.1	n.5364G>A		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes AF: 0.00128 AC: 195 AN: 152194 Hom.: 6 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0336

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.00267 AC: 660 AN: 247636 Hom.: 6 AF XY: 0.00242 AC XY: 326 AN XY: 134608

Gnomad AFR exome AF: 0.0000650

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0335

Gnomad SAS exome AF: 0.00144

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000444

Gnomad OTH exome AF: 0.00116

GnomAD4 exome AF: 0.000809 AC: 1182 AN: 1460886 Hom.: 13 Cov.: 31 AF XY: 0.000819 AC XY: 595 AN XY: 726642

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0223

Gnomad4 SAS exome AF: 0.00163

Gnomad4 FIN exome AF: 0.0000381

Gnomad4 NFE exome AF: 0.0000531

Gnomad4 OTH exome AF: 0.00149

GnomAD4 genome AF: 0.00129 AC: 196 AN: 152312 Hom.: 6 Cov.: 33 AF XY: 0.00164 AC XY: 122 AN XY: 74470

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.0000653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0339

Gnomad4 SAS AF: 0.00228

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00240 Hom.: 6

Bravo AF: 0.00171

ExAC AF: 0.00269 AC: 326

Asia WGS AF: 0.00924 AC: 32 AN: 3476

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 3 Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Benign, criteria provided, single submitter	case-control	Molecular Diagnosis Center for Deafness	-	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 06, 2013	Gly1220Arg in exon 3 of MYO15A: This variant is not expected to have clinical si gnificance because it has been identified in 1% (22/2178) of chromosomes by the 1000 Genomes Project (dbSNP rs146754758) and most mammals, including other prima tes, carry an arginine (Arg) at this position. -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 02, 2019	This variant is associated with the following publications: (PMID: 23865914) -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.059
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.30
Cadd	Benign	6.7
Dann	Benign	0.50
DEOGEN2	Benign	0.023	T;T;T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.035	T;.;T
MetaRNN	Benign	0.0034	T;T;T
MetaSVM	Benign	-0.67	T
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.21	T
Sift4G	Benign	0.93	T;T;.
Polyphen		0.0010	.;B;B
Vest4		0.15
MVP		0.25
ClinPred		0.0070	T
GERP RS		0.65
Varity_R		0.039
gMVP		0.43

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: rs146754758; hg19: chr17-18027845; COSMIC: COSV52759558;