rs116833707

chr17-18159299-G-Achr17-18159299-G-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP6

The NM_016239.4(MYO15A):c.9181G>A(p.Glu3061Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000158 in 1,614,000 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. E3061E) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00078 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000093 (0 hom.)
• Consequence: MYO15A NM_016239.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:2
• Conservation: PhyloP100: 9.24

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 -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.015765399).
• BP6: Variant 17-18159299-G-A is Benign according to our data. Variant chr17-18159299-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 228972.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=3}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYO15A	NM_016239.4	c.9181G>A	p.Glu3061Lys	missense_variant	54/66	ENST00000647165.2
MYO15A	XM_017024715.3	c.9184G>A	p.Glu3062Lys	missense_variant	52/64
MYO15A	XM_017024714.3	c.9121G>A	p.Glu3041Lys	missense_variant	51/63

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYO15A	ENST00000647165.2	c.9181G>A	p.Glu3061Lys	missense_variant	54/66		NM_016239.4	P1

Frequencies

GnomAD3 genomes AF: 0.000783 AC: 119 AN: 152004 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00281

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000184 AC: 46 AN: 249540 Hom.: 0 AF XY: 0.000118 AC XY: 16 AN XY: 135396

Gnomad AFR exome AF: 0.00271

Gnomad AMR exome AF: 0.0000869

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000883

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000930 AC: 136 AN: 1461878 Hom.: 0 Cov.: 32 AF XY: 0.0000756 AC XY: 55 AN XY: 727234

Gnomad4 AFR exome AF: 0.00358

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000629

Gnomad4 OTH exome AF: 0.0000993

GnomAD4 genome AF: 0.000782 AC: 119 AN: 152122 Hom.: 0 Cov.: 32 AF XY: 0.000968 AC XY: 72 AN XY: 74382

Gnomad4 AFR AF: 0.00280

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000116 Hom.: 0

Bravo AF: 0.000880

ESP6500AA AF: 0.00238 AC: 10

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000207 AC: 25

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 11, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 14, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 04, 2020	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Dec 11, 2017

Variant classified as Uncertain Significance - Favor Benign. The p.Glu3061Lys va riant in MYO15A has been previously reported by our laboratory in two individual s with hearing loss, but a variant affecting the second copy of the gene was not identified in either individual. This variant has been identified in 0.28% (66/ 23988) of African chromosomes by the Genome Aggregation Database (gnomAD, http:/ /gnomad.broadinstitute.org; dbSNP rs116833707). Although this variant has been s een in the general population, its frequency is not high enough to rule out a pa thogenic role. Computational prediction tools and conservation analysis do not p rovide strong support for or against an impact to the protein. In summary, while the clinical significance of the p.Glu3061Lys variant is uncertain, its frequen cy in the general population suggests that it is more likely to be benign. ACMG/ AMP Criteria applied: BS1_Supporting. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Uncertain	0.0
Cadd	Pathogenic	26
Dann	Uncertain	0.99
DEOGEN2	Benign	0.022	T;T;T;.;.;.;.
Eigen	Benign	0.15
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.91	D;.;D;D;D;D;T
M_CAP	Uncertain	0.19	D
MetaRNN	Benign	0.016	T;T;T;T;T;T;T
MetaSVM	Uncertain	0.31	D
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.53	T
Sift4G	Uncertain	0.0050	D;D;.;D;.;D;D
Polyphen		0.98	.;D;D;.;.;.;.
Vest4		0.34
MVP		0.86
ClinPred		0.078	T
GERP RS		4.9
Varity_R		0.19
gMVP		0.21

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: rs116833707; hg19: chr17-18062613; COSMIC: COSV52760978; COSMIC: COSV52760978;