rs201618718

chr17-18124495-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The NM_016239.4(MYO15A):c.3622C>T(p.Arg1208Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000842 in 1,612,292 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1208H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00064 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00086 (2 hom.)
• Consequence: MYO15A NM_016239.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:1
• Conservation: PhyloP100: 0.916

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.

• BP4: Computational evidence support a benign effect (MetaRNN=0.027741909).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYO15A	NM_016239.4	c.3622C>T	p.Arg1208Cys	missense_variant	3/66	ENST00000647165.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYO15A	ENST00000647165.2	c.3622C>T	p.Arg1208Cys	missense_variant	3/66		NM_016239.4	P1
MYO15A	ENST00000651088.1	c.163C>T	p.Arg55Cys	missense_variant	2/2
MYO15A	ENST00000583079.1	n.5328C>T		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes AF: 0.000637 AC: 97 AN: 152196 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00157

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000823

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.000842 AC: 208 AN: 246934 Hom.: 0 AF XY: 0.00102 AC XY: 137 AN XY: 134284

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000261

Gnomad ASJ exome AF: 0.000798

Gnomad EAS exome AF: 0.000167

Gnomad SAS exome AF: 0.00196

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00111

Gnomad OTH exome AF: 0.000498

GnomAD4 exome AF: 0.000863 AC: 1260 AN: 1459978 Hom.: 2 Cov.: 31 AF XY: 0.000917 AC XY: 666 AN XY: 726196

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.000537

Gnomad4 ASJ exome AF: 0.000574

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.00241

Gnomad4 FIN exome AF: 0.0000194

Gnomad4 NFE exome AF: 0.000871

Gnomad4 OTH exome AF: 0.000563

GnomAD4 genome AF: 0.000637 AC: 97 AN: 152314 Hom.: 0 Cov.: 33 AF XY: 0.000779 AC XY: 58 AN XY: 74476

Gnomad4 AFR AF: 0.000168

Gnomad4 AMR AF: 0.00157

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000823

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000776 Hom.: 0

Bravo AF: 0.000816

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.000231 AC: 1

ESP6500EA AF: 0.000821 AC: 7

ExAC AF: 0.000792 AC: 96

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000654

EpiControl AF: 0.00113

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 3 Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Al Jalila Children's Genomics Center, Al Jalila Childrens Speciality Hospital	Nov 01, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 08, 2018	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

not provided Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Aug 30, 2022	BS1_supporting -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jul 24, 2023	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 11, 2018

Variant classified as Uncertain Significance - Favor Benign. The p.Arg1208Cys va riant in MYO15A has been previously identified by our laboratory in two individu als with hearing loss; however, a variant in trans was not identied in either of these individuals. This variant has been identified in 0.2% (60/30752) of South Asian chromosomes and 0.1% (132/126234) of European chromosomes by the Genome A ggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs201618718 ). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. Computational prediction tools and conservation analysis do not provide strong support for or against an impac t to the protein; however, arginine at position 1208 is not conserved and severa l evolutionarily distant species carry a cysteine, raising the possibility that this change may be tolerated. In summary, while the clinical significance of the p.Arg1208Cys variant is uncertain, its lack of conservation suggests that it is more likely to be benign. ACMG/AMP Criteria applied: BP4 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.027	T
BayesDel_noAF	Pathogenic	0.18
Cadd	Uncertain	23
Dann	Uncertain	1.0
DEOGEN2	Benign	0.064	T;T;T
Eigen	Uncertain	0.22
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.82	T;.;T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.028	T;T;T
MetaSVM	Uncertain	0.60	D
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.38	T
Sift4G	Uncertain	0.058	T;T;.
Polyphen		0.68	.;P;P
Vest4		0.45
MVP		0.86
ClinPred		0.068	T
GERP RS		5.3
Varity_R		0.32
gMVP		0.66

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: rs201618718; hg19: chr17-18027809; COSMIC: COSV52765935;