17-18148133-C-T

Variant names:

• chr17-18148133-C-T
• rs121908970
• NM_016239.4:c.6614C>T

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 2P and 13B. PM1 BP4_Strong BP6 BS1 BS2

The NM_016239.4(MYO15A):​c.6614C>T​(p.Thr2205Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00441 in 1,613,862 control chromosomes in the GnomAD database, including 28 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0040 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0044 (26 hom.)
• Consequence: MYO15A NM_016239.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1 B:6
• Conservation: PhyloP100: 4.57
• Publications: 25 publications found

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]

MYO15A Gene-Disease associations (from GenCC):

• autosomal recessive nonsyndromic hearing loss 3

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), PanelApp Australia
• nonsyndromic genetic hearing loss

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -11 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 3 uncertain in NM_016239.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.011911124).
• BP6: Variant 17-18148133-C-T is Benign according to our data. Variant chr17-18148133-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 6956.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.004 (609/152352) while in subpopulation NFE AF = 0.00481 (327/68032). AF 95% confidence interval is 0.00438. There are 2 homozygotes in GnomAd4. There are 322 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016239.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYO15A	NM_016239.4	MANE Select	c.6614C>T	p.Thr2205Ile	missense	Exon 31 of 66	NP_057323.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYO15A	ENST00000647165.2	MANE Select	c.6614C>T	p.Thr2205Ile	missense	Exon 31 of 66	ENSP00000495481.1
	MYO15A	ENST00000578999.1	TSL:5	n.199C>T		non_coding_transcript_exon	Exon 2 of 4

Frequencies

GnomAD3 genomes AF: 0.00400 AC: 609 AN: 152234 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000699

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00124

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.0203

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00481

Gnomad OTH AF: 0.00430

GnomAD2 exomes AF: 0.00430 AC: 1072 AN: 249018 AF XY: 0.00429

Gnomad AFR exome AF: 0.000194

Gnomad AMR exome AF: 0.00101

Gnomad ASJ exome AF: 0.000199

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0194

Gnomad NFE exome AF: 0.00471

Gnomad OTH exome AF: 0.00462

GnomAD4 exome AF: 0.00445 AC: 6503 AN: 1461510 Hom.: 26 Cov.: 32 AF XY: 0.00439 AC XY: 3189 AN XY: 727064

African (AFR) AF: 0.000418 AC: 14 AN: 33480

American (AMR) AF: 0.00123 AC: 55 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000765 AC: 2 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00181 AC: 156 AN: 86250

European-Finnish (FIN) AF: 0.0178 AC: 947 AN: 53070

Middle Eastern (MID) AF: 0.00104 AC: 6 AN: 5768

European-Non Finnish (NFE) AF: 0.00455 AC: 5061 AN: 1111998

Other (OTH) AF: 0.00434 AC: 262 AN: 60390

GnomAD4 genome AF: 0.00400 AC: 609 AN: 152352 Hom.: 2 Cov.: 32 AF XY: 0.00432 AC XY: 322 AN XY: 74496

African (AFR) AF: 0.000697 AC: 29 AN: 41592

American (AMR) AF: 0.00124 AC: 19 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00186 AC: 9 AN: 4830

European-Finnish (FIN) AF: 0.0203 AC: 216 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00481 AC: 327 AN: 68032

Other (OTH) AF: 0.00426 AC: 9 AN: 2114

Alfa AF: 0.00345 Hom.: 2

Bravo AF: 0.00244

TwinsUK AF: 0.00431 AC: 16

ALSPAC AF: 0.00571 AC: 22

ESP6500AA AF: 0.000494 AC: 2

ESP6500EA AF: 0.00395 AC: 33

ExAC AF: 0.00417 AC: 504

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00409

EpiControl AF: 0.00480

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:3

Apr 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

MYO15A: BS2

Apr 23, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 30245029, 11735029, 17546645, 12545186, 23208854, 26308726, 27375115, 30579064)

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Benign:2

Dec 19, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Thr2205Ile variant in exon 31 of MYO15A: This variant is not expected to have cl inical significance because it has been identified in has been reported in 0.4% (33/8348) of European American chromosomes chromosomes from a broad population b y the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP r s121908970). It has been reported in the hemizygous state in an individual with Smith-Lemli-Opitz sydnrome (Liburd 2001) and homozygous in one individual with hearing loss who also carries a homozygous nonsense variant in MYO15A (Nal 2007) ; however, these reports are likely due to the frequency of this variant and not a reflection of its role in hearing loss.

Mar 21, 2016

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Deafness, with smith-magenis syndrome Pathogenic:1

Nov 01, 2001

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Autosomal recessive nonsyndromic hearing loss 3 Uncertain:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

Nonsyndromic genetic hearing loss Benign:1

Jan 05, 2024

Molecular Genetics, Royal Melbourne Hospital

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as Likely benign. Following criteria are met: BS1 - BS1: Allele frequency is greater than expected for disorder PP3 - PP3: Computational evidence support a deleterious effect on the gene or gene product (REVEL >=0.644 & <0.932 OR SpliceAI >0.50)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.050	T
BayesDel_noAF	Pathogenic	0.16
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.11	T
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.64	T
MetaRNN	Benign	0.012	T
MetaSVM	Uncertain	0.74	D
MutationAssessor	Pathogenic	2.9	M
PhyloP100		4.6
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-4.3	D
REVEL	Pathogenic	0.80
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0020	D
Polyphen		0.99	D
Vest4		0.54
MVP		0.89
ClinPred		0.045	T
GERP RS		3.1
Varity_R		0.29
gMVP		0.44
Mutation Taster		=32/68	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
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

Other links and lift over

dbSNP: rs121908970; hg19: chr17-18051447; COSMIC: COSV52754600;