rs146633221

chr17-18143935-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The NM_016239.4(MYO15A):c.6112C>T(p.Arg2038Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000377 in 1,610,906 control chromosomes in the GnomAD database, including 3 homozygotes. 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 Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2038H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00039 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00038 (2 hom.)
• Consequence: MYO15A NM_016239.4 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 2.21

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.017080843).
• BP6: Variant 17-18143935-C-T is Benign according to our data. Variant chr17-18143935-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 164538.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-18143935-C-T is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYO15A	NM_016239.4	c.6112C>T	p.Arg2038Cys	missense_variant	28/66	ENST00000647165.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYO15A	ENST00000647165.2	c.6112C>T	p.Arg2038Cys	missense_variant	28/66		NM_016239.4	P1

Frequencies

GnomAD3 genomes AF: 0.000394 AC: 60 AN: 152232 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000603

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000445 AC: 108 AN: 242794 Hom.: 0 AF XY: 0.000493 AC XY: 65 AN XY: 131936

Gnomad AFR exome AF: 0.000204

Gnomad AMR exome AF: 0.000647

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000337

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000621

Gnomad OTH exome AF: 0.000843

GnomAD4 exome AF: 0.000376 AC: 548 AN: 1458556 Hom.: 2 Cov.: 35 AF XY: 0.000381 AC XY: 276 AN XY: 725156

Gnomad4 AFR exome AF: 0.000239

Gnomad4 AMR exome AF: 0.000699

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000211

Gnomad4 FIN exome AF: 0.0000190

Gnomad4 NFE exome AF: 0.000383

Gnomad4 OTH exome AF: 0.000497

GnomAD4 genome AF: 0.000394 AC: 60 AN: 152350 Hom.: 1 Cov.: 33 AF XY: 0.000403 AC XY: 30 AN XY: 74500

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.000653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000603

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000568 Hom.: 0

Bravo AF: 0.000336

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00107 AC: 9

ExAC AF: 0.000537 AC: 65

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 31, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2023	MYO15A: BP4 -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Aug 29, 2013

Arg2038Cys in Exon 28 of MYO15A: This variant is not expected to have clinical s ignificance because it has been identified in 0.2% (14/7692) of Latino chromosom es by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; db SNP rs146633221), and the Arginine (Arg) at position 2038 is not conserved in ma mmals or evolutionarily distant species and the change to Cysteine (Cys) is pres ent in several species including rat and mouse. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.33
Cadd	Benign	20
Dann	Uncertain	0.99
DEOGEN2	Benign	0.090	T;D;D
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.11
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.82	T;.;T
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.017	T;T;T
MetaSVM	Benign	-0.48	T
MutationTaster	Benign	0.99	D
PrimateAI	Benign	0.42	T
Sift4G	Benign	0.10	T;T;.
Polyphen		0.018	.;B;B
Vest4		0.18
MVP		0.67
ClinPred		0.065	T
GERP RS		4.3
Varity_R		0.12
gMVP		0.30

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: rs146633221; hg19: chr17-18047249;