rs117612144

Positions:

• chr17-18121826-C-A
• chr17-18121826-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_016239.4(MYO15A):​c.3026C>A​(p.Pro1009His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00333 in 1,612,882 control chromosomes in the GnomAD database, including 69 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0037 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0033 (67 hom.)
• Consequence: MYO15A NM_016239.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1 B:5
• Conservation: PhyloP100: 0.0910

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006921023).
• BP6: Variant 17-18121826-C-A is Benign according to our data. Variant chr17-18121826-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 226782.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-18121826-C-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00373 (568/152306) while in subpopulation EAS AF= 0.0342 (177/5174). AF 95% confidence interval is 0.0301. There are 2 homozygotes in gnomad4. There are 342 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYO15A	NM_016239.4	c.3026C>A	p.Pro1009His	missense_variant	2/66	ENST00000647165.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYO15A	ENST00000647165.2	c.3026C>A	p.Pro1009His	missense_variant	2/66		NM_016239.4	P1
MYO15A	ENST00000583079.1	n.2659C>A		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes AF: 0.00373 AC: 567 AN: 152188 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0339

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.0216

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00206

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00591 AC: 1466 AN: 247930 Hom.: 26 AF XY: 0.00568 AC XY: 767 AN XY: 135008

Gnomad AFR exome AF: 0.000131

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.000200

Gnomad EAS exome AF: 0.0409

Gnomad SAS exome AF: 0.000425

Gnomad FIN exome AF: 0.0198

Gnomad NFE exome AF: 0.00234

Gnomad OTH exome AF: 0.00365

GnomAD4 exome AF: 0.00329 AC: 4807 AN: 1460576 Hom.: 67 Cov.: 44 AF XY: 0.00327 AC XY: 2374 AN XY: 726574

Gnomad4 AFR exome AF: 0.000149

Gnomad4 AMR exome AF: 0.000224

Gnomad4 ASJ exome AF: 0.000115

Gnomad4 EAS exome AF: 0.0470

Gnomad4 SAS exome AF: 0.000556

Gnomad4 FIN exome AF: 0.0189

Gnomad4 NFE exome AF: 0.00155

Gnomad4 OTH exome AF: 0.00268

GnomAD4 genome AF: 0.00373 AC: 568 AN: 152306 Hom.: 2 Cov.: 33 AF XY: 0.00459 AC XY: 342 AN XY: 74464

Gnomad4 AFR AF: 0.000192

Gnomad4 AMR AF: 0.000261

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0342

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.0216

Gnomad4 NFE AF: 0.00206

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00342 Hom.: 3

Bravo AF: 0.00250

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00267 AC: 22

ExAC AF: 0.00613 AC: 740

Asia WGS AF: 0.0120 AC: 40 AN: 3478

EpiCase AF: 0.00218

EpiControl AF: 0.00279

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:1 Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 30, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2023	MYO15A: BP4, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

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

Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Pathogenic, flagged submission	clinical testing	Molecular Diagnosis Center for Deafness	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Nov 12, 2015

p.Pro1009His in exon 2 of MYO15A: This variant was reported as homozygous in one Chinese (Hans) individual with hearing loss (Yang 2013); however, it is not e xpected to have clinical significance because it has been identified in 4.6% (39 5/8578) of East Asian chromosomes, including 14 homozygous individuals, by the E xome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs11761 2144). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	16
DANN	Benign	0.96
DEOGEN2	Benign	0.036	T;T;T
Eigen	Benign	-0.73
Eigen_PC	Benign	-0.83
FATHMM_MKL	Benign	0.095	N
LIST_S2	Benign	0.52	T;.;T
MetaRNN	Benign	0.0069	T;T;T
MetaSVM	Benign	-0.62	T
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.32	T
Sift4G	Uncertain	0.0050	D;D;.
Polyphen		0.97	.;D;D
Vest4		0.48
MVP		0.68
ClinPred		0.043	T
GERP RS		0.42
Varity_R		0.14
gMVP		0.18

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: rs117612144; hg19: chr17-18025140; COSMIC: COSV52754356;