rs16926628

Variant names:

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBA1

The NM_017433.5(MYO3A):c.3112-4T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.11 in 1,610,790 control chromosomes in the GnomAD database, including 10,752 homozygotes. In-silico tool predicts 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 (★★).

Frequency

Genomes: 𝑓 0.12 ( 1317 hom., cov: 33)

Exomes 𝑓: 0.11 ( 9435 hom. )

Consequence

MYO3A
NM_017433.5 splice_region, intron

Scores

Splicing: ADA: 0.0001928

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.378

Publications

7 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 -18 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.45).

BP6

Variant 10-26168708-T-C is Benign according to our data. Variant chr10-26168708-T-C is described in ClinVar as Benign. ClinVar VariationId is 45807.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 link	c.3112-4T>C		splice_region_variant, intron_variant	Intron 27 of 34	ENST00000642920.2	NP_059129.3

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein
MYO3A	ENST00000642920.2 link	c.3112-4T>C	splice_region_variant, intron_variant	Intron 27 of 34		NM_017433.5	ENSP00000495965.1
MYO3A	ENST00000543632.5 link	c.1777-43135T>C	intron_variant	Intron 16 of 16	1		ENSP00000445909.1
MYO3A	ENST00000477691.2 link	n.338-4T>C	splice_region_variant, intron_variant	Intron 1 of 1	2
MYO3A	ENST00000647478.1 link	n.*1107-4T>C	splice_region_variant, intron_variant	Intron 25 of 29			ENSP00000493932.1

Frequencies

GnomAD3 genomes

AF:

0.124

AC:

18787

AN:

152100

Hom.:

1316

Cov.:

show subpopulations

Gnomad AFR

AF:

0.172

Gnomad AMI

AF:

0.175

Gnomad AMR

AF:

0.0876

Gnomad ASJ

AF:

0.0778

Gnomad EAS

AF:

0.00192

Gnomad SAS

AF:

0.0345

Gnomad FIN

AF:

0.128

Gnomad MID

AF:

0.0823

Gnomad NFE

AF:

0.119

Gnomad OTH

AF:

0.106

GnomAD2 exomes

AF:

0.0925

AC:

23169

AN:

250372

AF XY:

0.0912

show subpopulations

Gnomad AFR exome

AF:

0.175

Gnomad AMR exome

AF:

0.0511

Gnomad ASJ exome

AF:

0.0742

Gnomad EAS exome

AF:

0.00234

Gnomad FIN exome

AF:

0.123

Gnomad NFE exome

AF:

0.119

Gnomad OTH exome

AF:

0.0832

GnomAD4 exome

AF:

0.108

AC:

157964

AN:

1458572

Hom.:

9435

Cov.:

AF XY:

0.106

AC XY:

77034

AN XY:

725760

show subpopulations

African (AFR)

AF:

0.172

AC:

5762

AN:

33414

American (AMR)

AF:

0.0536

AC:

2394

AN:

44702

Ashkenazi Jewish (ASJ)

AF:

0.0755

AC:

1972

AN:

26104

East Asian (EAS)

AF:

0.00136

AC:

AN:

39598

South Asian (SAS)

AF:

0.0370

AC:

3188

AN:

86164

European-Finnish (FIN)

AF:

0.123

AC:

6469

AN:

52788

Middle Eastern (MID)

AF:

0.0688

AC:

371

AN:

5396

European-Non Finnish (NFE)

AF:

0.119

AC:

131620

AN:

1110142

Other (OTH)

AF:

0.102

AC:

6134

AN:

60264

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

6426

12852

19277

25703

32129

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4708

9416

14124

18832

23540

<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:

0.124

AC:

18799

AN:

152218

Hom.:

1317

Cov.:

AF XY:

0.122

AC XY:

9044

AN XY:

74430

show subpopulations

African (AFR)

AF:

0.172

AC:

7144

AN:

41532

American (AMR)

AF:

0.0874

AC:

1336

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.0778

AC:

270

AN:

3470

East Asian (EAS)

AF:

0.00193

AC:

AN:

5188

South Asian (SAS)

AF:

0.0344

AC:

166

AN:

4832

European-Finnish (FIN)

AF:

0.128

AC:

1359

AN:

10590

Middle Eastern (MID)

AF:

0.0850

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.119

AC:

8108

AN:

68000

Other (OTH)

AF:

0.105

AC:

221

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

837

1673

2510

3346

4183

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

198

396

594

792

990

<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:

0.114

Hom.:

2036

Bravo

AF:

0.125

Asia WGS

AF:

0.0270

AC:

AN:

3476

EpiCase

AF:

0.110

EpiControl

AF:

0.114

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

May 07, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

3112-4T>C in Intron 27 of MYO3A: This variant is not expected to have clinical s ignificance because it is not located within the conserved splice consensus sequ ence and has been identified in 17.3% (647/3738) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.wa shington.edu/EVS; dbSNP rs16926628). -

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. -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Autosomal recessive nonsyndromic hearing loss 30

Benign:1

Feb 27, 2019

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.45

CADD

Benign

(source)

DANN

Benign

0.72

PhyloP100

0.38

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00019

dbscSNV1_RF

Benign

0.010

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

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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