rs143826293

Positions:

• chr17-18155224-C-T

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.8339C>T​(p.Thr2780Met) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00148 in 1,613,956 control chromosomes in the GnomAD database, including 54 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. T2780T) has been classified as Pathogenic.

• Frequency:
  • Genomes: 𝑓 0.0039 (20 hom., cov: 33)
  • Exomes 𝑓: 0.0012 (34 hom.)
• Consequence: MYO15A NM_016239.4 missense, splice_region
• Scores: Splicing: ADA: 0.01123
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 4.40

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]

LOC105371567 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00789547).
• BP6: Variant 17-18155224-C-T is Benign according to our data. Variant chr17-18155224-C-T is described in ClinVar as [Benign]. Clinvar id is 45768.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00389 (593/152316) while in subpopulation AMR AF= 0.0364 (557/15302). AF 95% confidence interval is 0.0339. There are 20 homozygotes in gnomad4. There are 371 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 20 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYO15A	NM_016239.4	c.8339C>T	p.Thr2780Met	missense_variant, splice_region_variant	46/66	ENST00000647165.2	NP_057323.3
LOC105371567	XR_001752809.1	n.89+28G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYO15A	ENST00000647165.2	c.8339C>T	p.Thr2780Met	missense_variant, splice_region_variant	46/66		NM_016239.4	ENSP00000495481	P1

Frequencies

GnomAD3 genomes AF: 0.00390 AC: 594 AN: 152198 Hom.: 20 Cov.: 33

Gnomad AFR AF: 0.000362

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0365

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00526

GnomAD3 exomes AF: 0.00519 AC: 1292 AN: 249162 Hom.: 24 AF XY: 0.00403 AC XY: 545 AN XY: 135296

Gnomad AFR exome AF: 0.000518

Gnomad AMR exome AF: 0.0363

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000556

Gnomad SAS exome AF: 0.000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000796

Gnomad OTH exome AF: 0.00215

GnomAD4 exome AF: 0.00123 AC: 1795 AN: 1461640 Hom.: 34 Cov.: 34 AF XY: 0.00108 AC XY: 784 AN XY: 727136

Gnomad4 AFR exome AF: 0.000508

Gnomad4 AMR exome AF: 0.0358

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000313

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000719

Gnomad4 OTH exome AF: 0.00113

GnomAD4 genome AF: 0.00389 AC: 593 AN: 152316 Hom.: 20 Cov.: 33 AF XY: 0.00498 AC XY: 371 AN XY: 74482

Gnomad4 AFR AF: 0.000361

Gnomad4 AMR AF: 0.0364

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.00520

Alfa AF: 0.000595 Hom.: 0

Bravo AF: 0.00609

ExAC AF: 0.00336 AC: 407

EpiCase AF: 0.000164

EpiControl AF: 0.00

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 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	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 04, 2015	p.Thr2780Met in exon 46 of MYO15A: This variant is not expected to have clinical significance because it has been identified in 3.4% (391/11528) of Latino chrom osomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org ; dbSNP rs143826293). -

Autosomal recessive nonsyndromic hearing loss 3 Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 01, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Oct 29, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	21
DANN	Benign	0.88
DEOGEN2	Benign	0.034	T;T;T;.;.
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.22
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.78	T;.;T;T;T
MetaRNN	Benign	0.0079	T;T;T;T;T
MetaSVM	Benign	-0.70	T
MutationAssessor	Benign	0.92	.;L;L;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-1.8	.;N;.;.;.
REVEL	Uncertain	0.32
Sift	Benign	0.38	.;T;.;.;.
Sift4G	Benign	0.12	T;T;.;T;.
Polyphen		0.46	.;P;P;.;.
Vest4		0.15
MVP		0.67
ClinPred		0.019	T
GERP RS		3.3
Varity_R		0.023
gMVP		0.31

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.011
dbscSNV1_RF	Benign	0.088
SpliceAI score (max)		0.020		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: rs143826293; hg19: chr17-18058538;