rs35379457

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_017433.5(MYO3A):c.1104C>T(p.Tyr368Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.52 in 1,585,094 control chromosomes in the GnomAD database, including 220,702 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.47 ( 17865 hom., cov: 33)

Exomes 𝑓: 0.53 ( 202837 hom. )

Consequence

MYO3A
NM_017433.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -0.123

Publications

14 publications found

Variant links:

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

MYO3A links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.38).

BP6

Variant 10-26068818-C-T is Benign according to our data. Variant chr10-26068818-C-T is described in ClinVar as Benign. ClinVar VariationId is 45796.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.123 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.55 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYO3A	NM_017433.5 link	c.1104C>T	p.Tyr368Tyr	synonymous_variant	Exon 12 of 35	ENST00000642920.2	NP_059129.3	Q8NEV4-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
MYO3A	ENST00000642920.2 link	c.1104C>T	p.Tyr368Tyr	synonymous_variant	Exon 12 of 35		NM_017433.5	ENSP00000495965.1	Q8NEV4-1
MYO3A	ENST00000543632.5 link	c.1104C>T	p.Tyr368Tyr	synonymous_variant	Exon 11 of 17	1		ENSP00000445909.1	F5H0U9
MYO3A	ENST00000642197.1 link	n.1308C>T		non_coding_transcript_exon_variant	Exon 12 of 27
MYO3A	ENST00000647478.1 link	n.1104C>T		non_coding_transcript_exon_variant	Exon 11 of 30			ENSP00000493932.1	A0A2R8Y4D5

Frequencies

GnomAD3 genomes

AF:

0.475

AC:

71993

AN:

151654

Hom.:

17861

Cov.:

show subpopulations

Gnomad AFR

AF:

0.359

Gnomad AMI

AF:

0.433

Gnomad AMR

AF:

0.410

Gnomad ASJ

AF:

0.533

Gnomad EAS

AF:

0.271

Gnomad SAS

AF:

0.493

Gnomad FIN

AF:

0.578

Gnomad MID

AF:

0.602

Gnomad NFE

AF:

0.555

Gnomad OTH

AF:

0.476

GnomAD2 exomes

AF:

0.478

AC:

119851

AN:

250570

AF XY:

0.490

show subpopulations

Gnomad AFR exome

AF:

0.353

Gnomad AMR exome

AF:

0.318

Gnomad ASJ exome

AF:

0.528

Gnomad EAS exome

AF:

0.271

Gnomad FIN exome

AF:

0.579

Gnomad NFE exome

AF:

0.553

Gnomad OTH exome

AF:

0.504

GnomAD4 exome

AF:

0.525

AC:

752551

AN:

1433324

Hom.:

202837

Cov.:

AF XY:

0.526

AC XY:

375451

AN XY:

714322

show subpopulations

African (AFR)

AF:

0.356

AC:

11759

AN:

33034

American (AMR)

AF:

0.330

AC:

14704

AN:

44576

Ashkenazi Jewish (ASJ)

AF:

0.520

AC:

13445

AN:

25842

East Asian (EAS)

AF:

0.262

AC:

10334

AN:

39448

South Asian (SAS)

AF:

0.482

AC:

41232

AN:

85620

European-Finnish (FIN)

AF:

0.575

AC:

30508

AN:

53058

Middle Eastern (MID)

AF:

0.555

AC:

3168

AN:

5704

European-Non Finnish (NFE)

AF:

0.549

AC:

596928

AN:

1086626

Other (OTH)

AF:

0.513

AC:

30473

AN:

59416

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.424

Heterozygous variant carriers

16509

33019

49528

66038

82547

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

16336

32672

49008

65344

81680

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.474

AC:

72009

AN:

151770

Hom.:

17865

Cov.:

AF XY:

0.474

AC XY:

35133

AN XY:

74148

show subpopulations

African (AFR)

AF:

0.359

AC:

14888

AN:

41436

American (AMR)

AF:

0.409

AC:

6235

AN:

15252

Ashkenazi Jewish (ASJ)

AF:

0.533

AC:

1843

AN:

3456

East Asian (EAS)

AF:

0.271

AC:

1402

AN:

5170

South Asian (SAS)

AF:

0.492

AC:

2375

AN:

4828

European-Finnish (FIN)

AF:

0.578

AC:

6084

AN:

10524

Middle Eastern (MID)

AF:

0.586

AC:

171

AN:

292

European-Non Finnish (NFE)

AF:

0.555

AC:

37613

AN:

67794

Other (OTH)

AF:

0.476

AC:

1005

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

1874

3748

5621

7495

9369

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

660

1320

1980

2640

3300

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.521

Hom.:

11927

Bravo

AF:

0.451

Asia WGS

AF:

0.397

AC:

1380

AN:

3476

EpiCase

AF:

0.556

EpiControl

AF:

0.560

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

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. -

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

Significance:Benign

Review Status:no assertion criteria provided

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

Tyr368Tyr in Exon 12 of MYO3A: This variant is not expected to have clinical si gnificance because it does not alter an amino acid residue, is not located withi n the splice consensus sequence, and has been identified in 49.1% (3446/7020) of European American chromosomes from a broad population by the NHLBI Exome Sequen cing Project (http://evs.gs.washington.edu/EVS; dbSNP rs35379457). -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Autosomal recessive nonsyndromic hearing loss 30

Benign:2

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. -

Sep 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

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

-0.38

CADD

Benign

2.4

(source)

DANN

Benign

0.44

PhyloP100

-0.12

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over