rs200843771

Positions:

• chr17-18171649-A-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_016239.4(MYO15A):​c.10094A>G​(p.Gln3365Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000762 in 1,613,928 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00041 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000041 (0 hom.)
• Consequence: MYO15A NM_016239.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:1
• Conservation: PhyloP100: 4.39

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 -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.044311523).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYO15A	NM_016239.4	c.10094A>G	p.Gln3365Arg	missense_variant	63/66	ENST00000647165.2
MYO15A	XM_017024715.3	c.10097A>G	p.Gln3366Arg	missense_variant	61/64
MYO15A	XM_017024714.3	c.10034A>G	p.Gln3345Arg	missense_variant	60/63

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYO15A	ENST00000647165.2	c.10094A>G	p.Gln3365Arg	missense_variant	63/66		NM_016239.4	P1

Frequencies

GnomAD3 genomes AF: 0.000414 AC: 63 AN: 152194 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00150

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

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: 0.0000883 AC: 22 AN: 249154 Hom.: 0 AF XY: 0.0000665 AC XY: 9 AN XY: 135294

Gnomad AFR exome AF: 0.00136

Gnomad AMR exome AF: 0.0000290

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000411 AC: 60 AN: 1461616 Hom.: 0 Cov.: 32 AF XY: 0.0000316 AC XY: 23 AN XY: 727108

Gnomad4 AFR exome AF: 0.00152

Gnomad4 AMR exome AF: 0.0000447

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: 0.00000270

Gnomad4 OTH exome AF: 0.0000662

GnomAD4 genome AF: 0.000414 AC: 63 AN: 152312 Hom.: 0 Cov.: 32 AF XY: 0.000403 AC XY: 30 AN XY: 74488

Gnomad4 AFR AF: 0.00149

Gnomad4 AMR AF: 0.0000654

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: 0.000106 Hom.: 0

Bravo AF: 0.000540

ESP6500AA AF: 0.000489 AC: 2

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000107 AC: 13

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Apr 14, 2020	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Oct 13, 2016

Variant classified as Uncertain Significance - Favor Benign. The p.Gln3365Arg va riant in MYO15A has not been previously reported in individuals with hearing los s, but it has been identified in 0.1% (12/9576) of African chromosomes by the Ex ome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs200843 771). Although this variant has been seen in the general population, its frequen cy is not high enough to rule out a pathogenic role. The glutamine at position 3 365 is not conserved in mammals or evolutionary distant species; with 2 species (elephant and manatee) having an arginine (Arg) at this position supporting that a change at this position may be tolerated. Additional computational prediction tools do not provide strong support for or against an impact to the protein. I n summary, while the clinical significance of the p.Gln3365Arg variant is uncert ain, available data suggest that it is more likely to be benign. -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 31, 2020

The c.10094A>G (p.Q3365R) alteration is located in exon 63 (coding exon 62) of the MYO15A gene. This alteration results from an A to G substitution at nucleotide position 10094, causing the glutamine (Q) at amino acid position 3365 to be replaced by an arginine (R). Based on data from the Genome Aggregation Database (gnomAD) database, the MYO15A c.10094A>G alteration was observed in 0.01% (38/280546) of total alleles studied, with a frequency of 0.15% (37/24164) in the African subpopulation. This amino acid position is well conserved in available vertebrate species. The p.Q3365R alteration is predicted to be tolerated by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Autosomal recessive nonsyndromic hearing loss 3 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.014	T;T;T;.;.
Eigen	Benign	0.18
Eigen_PC	Benign	0.16
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.62	T;.;T;T;T
M_CAP	Pathogenic	0.43	D
MetaRNN	Benign	0.044	T;T;T;T;T
MetaSVM	Uncertain	0.77	D
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Benign	0.41	T
Sift4G	Uncertain	0.0090	D;D;.;D;.
Polyphen		0.018	.;B;B;.;.
Vest4		0.37
MVP		0.69
ClinPred		0.045	T
GERP RS		4.3
Varity_R		0.20
gMVP		0.23

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: rs200843771; hg19: chr17-18074963;