rs11014875

Variant names:

• chr10-25952096-T-A
• rs11014875
• NM_017433.5:c.-15T>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_017433.5(MYO3A):​c.-15T>A variant causes a splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0507 in 1,602,384 control chromosomes in the GnomAD database, including 2,965 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.081 (826 hom., cov: 32)
  • Exomes 𝑓: 0.047 (2139 hom.)
• Consequence: MYO3A NM_017433.5 splice_region
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.668
• Publications: 6 publications found

Genes affected

MYO3A (HGNC:7601): (myosin IIIA) The protein encoded by this gene belongs to the myosin superfamily. Myosins are actin-dependent motor proteins and are categorized into conventional myosins (class II) and unconventional myosins (classes I and III through XV) based on their variable C-terminal cargo-binding domains. Class III myosins, such as this one, have a kinase domain N-terminal to the conserved N-terminal motor domains and are expressed in photoreceptors. The protein encoded by this gene plays an important role in hearing in humans. Three different recessive, loss of function mutations in the encoded protein have been shown to cause nonsyndromic progressive hearing loss. Expression of this gene is highly restricted, with the strongest expression in retina and cochlea. [provided by RefSeq, Jul 2008]

MYO3A Gene-Disease associations (from GenCC):

• autosomal recessive nonsyndromic hearing loss 30

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

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• hearing loss, autosomal dominant 90

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 10-25952096-T-A is Benign according to our data. Variant chr10-25952096-T-A is described in ClinVar as Benign. ClinVar VariationId is 45791.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.169 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYO3A	NM_017433.5	c.-15T>A		splice_region_variant	Exon 3 of 35	ENST00000642920.2	NP_059129.3
MYO3A	NM_017433.5	c.-15T>A		5_prime_UTR_variant	Exon 3 of 35	ENST00000642920.2	NP_059129.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYO3A	ENST00000642920.2	c.-15T>A		splice_region_variant	Exon 3 of 35		NM_017433.5	ENSP00000495965.1
MYO3A	ENST00000642920.2	c.-15T>A		5_prime_UTR_variant	Exon 3 of 35		NM_017433.5	ENSP00000495965.1

Frequencies

GnomAD3 genomes AF: 0.0813 AC: 12359 AN: 152050 Hom.: 824 Cov.: 32

Gnomad AFR AF: 0.172

Gnomad AMI AF: 0.0385

Gnomad AMR AF: 0.0531

Gnomad ASJ AF: 0.0576

Gnomad EAS AF: 0.00193

Gnomad SAS AF: 0.0288

Gnomad FIN AF: 0.0384

Gnomad MID AF: 0.0791

Gnomad NFE AF: 0.0508

Gnomad OTH AF: 0.0733

GnomAD2 exomes AF: 0.0502 AC: 12512 AN: 249234 AF XY: 0.0488

Gnomad AFR exome AF: 0.170

Gnomad AMR exome AF: 0.0318

Gnomad ASJ exome AF: 0.0575

Gnomad EAS exome AF: 0.00256

Gnomad FIN exome AF: 0.0365

Gnomad NFE exome AF: 0.0538

Gnomad OTH exome AF: 0.0472

GnomAD4 exome AF: 0.0475 AC: 68870 AN: 1450216 Hom.: 2139 Cov.: 30 AF XY: 0.0470 AC XY: 33961 AN XY: 722110

African (AFR) AF: 0.170 AC: 5629 AN: 33102

American (AMR) AF: 0.0345 AC: 1536 AN: 44490

Ashkenazi Jewish (ASJ) AF: 0.0584 AC: 1516 AN: 25942

East Asian (EAS) AF: 0.00129 AC: 51 AN: 39442

South Asian (SAS) AF: 0.0311 AC: 2667 AN: 85704

European-Finnish (FIN) AF: 0.0359 AC: 1912 AN: 53202

Middle Eastern (MID) AF: 0.0722 AC: 394 AN: 5458

European-Non Finnish (NFE) AF: 0.0473 AC: 52195 AN: 1103000

Other (OTH) AF: 0.0496 AC: 2970 AN: 59876

GnomAD4 genome AF: 0.0814 AC: 12379 AN: 152168 Hom.: 826 Cov.: 32 AF XY: 0.0792 AC XY: 5894 AN XY: 74394

African (AFR) AF: 0.172 AC: 7145 AN: 41504

American (AMR) AF: 0.0530 AC: 810 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.0576 AC: 200 AN: 3472

East Asian (EAS) AF: 0.00193 AC: 10 AN: 5178

South Asian (SAS) AF: 0.0288 AC: 139 AN: 4822

European-Finnish (FIN) AF: 0.0384 AC: 408 AN: 10616

Middle Eastern (MID) AF: 0.0782 AC: 23 AN: 294

European-Non Finnish (NFE) AF: 0.0508 AC: 3456 AN: 67990

Other (OTH) AF: 0.0725 AC: 153 AN: 2110

Alfa AF: 0.0638 Hom.: 79

Bravo AF: 0.0866

Asia WGS AF: 0.0230 AC: 81 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

May 09, 2017

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

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PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 07, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

-15T>A in Exon 03 of MYO3A: This variant is not expected to have clinical signif icance because it has been identified in 16.8% (627/3736) of African American ch romosomes from a broad population by the NHLBI Exome Sequencing Project (http:// evs.gs.washingt -

Autosomal recessive nonsyndromic hearing loss 30 Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

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Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	10
DANN	Benign	0.61
PhyloP100		0.67
Mutation Taster		=276/24	polymorphism (auto)

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

Other links and lift over

dbSNP: rs11014875; hg19: chr10-26241025;