10-26067085-C-T

Variant names:

• chr10-26067085-C-T
• rs3824698
• NM_017433.5:c.1053+11C>T

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.1053+11C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.521 in 1,550,540 control chromosomes in the GnomAD database, including 215,466 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.47 (17828 hom., cov: 32)
  • Exomes 𝑓: 0.53 (197638 hom.)
• Consequence: MYO3A NM_017433.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -1.23
• Publications: 7 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=-0.83).
• BP6: Variant 10-26067085-C-T is Benign according to our data. Variant chr10-26067085-C-T is described in ClinVar as Benign. ClinVar VariationId is 45793.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.55 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017433.5. 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
	MYO3A	NM_017433.5	MANE Select	c.1053+11C>T		intron	N/A	NP_059129.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYO3A	ENST00000642920.2	MANE Select	c.1053+11C>T		intron	N/A	ENSP00000495965.1
	MYO3A	ENST00000543632.5	TSL:1	c.1053+11C>T		intron	N/A	ENSP00000445909.1
	MYO3A	ENST00000642197.1		n.1257+11C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.475 AC: 71957 AN: 151626 Hom.: 17823 Cov.: 32

Gnomad AFR AF: 0.359

Gnomad AMI AF: 0.428

Gnomad AMR AF: 0.409

Gnomad ASJ AF: 0.535

Gnomad EAS AF: 0.271

Gnomad SAS AF: 0.494

Gnomad FIN AF: 0.579

Gnomad MID AF: 0.608

Gnomad NFE AF: 0.554

Gnomad OTH AF: 0.477

GnomAD2 exomes AF: 0.477 AC: 118648 AN: 248680 AF XY: 0.488

Gnomad AFR exome AF: 0.352

Gnomad AMR exome AF: 0.317

Gnomad ASJ exome AF: 0.527

Gnomad EAS exome AF: 0.270

Gnomad FIN exome AF: 0.578

Gnomad NFE exome AF: 0.552

Gnomad OTH exome AF: 0.503

GnomAD4 exome AF: 0.526 AC: 735785 AN: 1398796 Hom.: 197638 Cov.: 24 AF XY: 0.526 AC XY: 368128 AN XY: 699216

African (AFR) AF: 0.358 AC: 11455 AN: 32030

American (AMR) AF: 0.329 AC: 14615 AN: 44384

Ashkenazi Jewish (ASJ) AF: 0.521 AC: 13350 AN: 25618

East Asian (EAS) AF: 0.262 AC: 10271 AN: 39230

South Asian (SAS) AF: 0.482 AC: 40814 AN: 84672

European-Finnish (FIN) AF: 0.575 AC: 30496 AN: 53032

Middle Eastern (MID) AF: 0.557 AC: 3131 AN: 5626

European-Non Finnish (NFE) AF: 0.551 AC: 581664 AN: 1055864

Other (OTH) AF: 0.514 AC: 29989 AN: 58340

GnomAD4 genome AF: 0.474 AC: 71975 AN: 151744 Hom.: 17828 Cov.: 32 AF XY: 0.474 AC XY: 35149 AN XY: 74154

African (AFR) AF: 0.359 AC: 14860 AN: 41392

American (AMR) AF: 0.408 AC: 6235 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.535 AC: 1854 AN: 3468

East Asian (EAS) AF: 0.272 AC: 1402 AN: 5158

South Asian (SAS) AF: 0.493 AC: 2377 AN: 4818

European-Finnish (FIN) AF: 0.579 AC: 6086 AN: 10516

Middle Eastern (MID) AF: 0.592 AC: 173 AN: 292

European-Non Finnish (NFE) AF: 0.554 AC: 37598 AN: 67828

Other (OTH) AF: 0.477 AC: 1003 AN: 2102

Alfa AF: 0.522 Hom.: 3953

Bravo AF: 0.451

Asia WGS AF: 0.398 AC: 1384 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Nov 20, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

1053+11C>T in Intron 11 of MYO3A: This variant is not expected to have clinical significance because it is not located within the conserved splice consensus seq uence and has been identified in 47.1% (3305/7020) of European American chromoso mes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs .washington.edu/EVS; dbSNP rs3824698).

Autosomal recessive nonsyndromic hearing loss 30 Benign:2

Sep 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 13, 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:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Jun 22, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.27
DANN	Benign	0.55
PhyloP100		-1.2
Mutation Taster		=100/0	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: rs3824698; hg19: chr10-26356014; COSMIC: COSV56348758;