rs1463824476

chr17-18122186-G-Achr17-18122186-G-C

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_016239.4(MYO15A):c.3386G>A(p.Arg1129Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000496 in 1,613,040 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: MYO15A NM_016239.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.39

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 -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.045826256).
• BP6: Variant 17-18122186-G-A is Benign according to our data. Variant chr17-18122186-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 505832.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYO15A	NM_016239.4	c.3386G>A	p.Arg1129Gln	missense_variant	2/66	ENST00000647165.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYO15A	ENST00000647165.2	c.3386G>A	p.Arg1129Gln	missense_variant	2/66		NM_016239.4	P1
MYO15A	ENST00000583079.1	n.3019G>A		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152232 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000121 AC: 3 AN: 248790 Hom.: 0 AF XY: 0.00000739 AC XY: 1 AN XY: 135266

Gnomad AFR exome AF: 0.0000649

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000557

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000887

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1460808 Hom.: 0 Cov.: 44 AF XY: 0.00000413 AC XY: 3 AN XY: 726712

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152232 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74368

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000675 Hom.: 0

Bravo AF: 0.0000151

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jun 18, 2017

p.Arg1129Gln in exon 2 of MYO15A: This variant is not expected to have clinical significance due to a lack of conservation across species, including mammals. Of note, 12 mammals have a glutamine (Gln) at this position despite high nearby am ino acid conservation. In addition, computational prediction tools do not sugges t a high likelihood of impact to the protein. It has also been identified in 1/5 468 chromosomes of unspecified ethnicity and 1/15239 African chromosomes by the Genome Aggregation Database (gnomAD, http://gnomAD.broadinstitute.org). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.48
Cadd	Benign	0.86
Dann	Benign	0.89
DEOGEN2	Benign	0.022	T;T;T
Eigen	Benign	-1.9
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.011	N
LIST_S2	Benign	0.61	T;.;T
M_CAP	Benign	0.072	D
MetaRNN	Benign	0.046	T;T;T
MetaSVM	Benign	-0.78	T
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.25	T
Sift4G	Benign	0.22	T;T;.
Polyphen		0.0030	.;B;B
Vest4		0.065
MutPred		0.28		Loss of MoRF binding (P = 0.014);Loss of MoRF binding (P = 0.014);Loss of MoRF binding (P = 0.014);
MVP		0.27
ClinPred		0.071	T
GERP RS		-10
Varity_R		0.030
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: rs1463824476; hg19: chr17-18025500; COSMIC: COSV52763539;