rs3824697

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_017433.5(MYO3A):c.1053+12A>G 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 1,546,196 control chromosomes in the GnomAD database, including 214,688 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.47 ( 17825 hom., cov: 32)

Exomes 𝑓: 0.53 ( 196863 hom. )

Consequence

MYO3A
NM_017433.5 intron

Scores

Clinical Significance

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

Conservation

PhyloP100: -1.16

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.84).

BP6

Variant 10-26067086-A-G is Benign according to our data. Variant chr10-26067086-A-G is described in ClinVar as [Benign]. Clinvar id is 45794.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-26067086-A-G is described in Lovd as [Benign].

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/exons	MANE	Protein	UniProt
MYO3A	NM_017433.5 linkuse as main transcript	c.1053+12A>G		intron_variant		ENST00000642920.2	NP_059129.3

Ensembl

Gene	Transcript	HGVSc	Effect	TSL	MANE	Protein	Appris	UniProt
MYO3A	ENST00000642920.2 linkuse as main transcript	c.1053+12A>G	intron_variant		NM_017433.5	ENSP00000495965	P1	Q8NEV4-1
MYO3A	ENST00000543632.5 linkuse as main transcript	c.1053+12A>G	intron_variant	1		ENSP00000445909
MYO3A	ENST00000647478.1 linkuse as main transcript	c.1053+12A>G	intron_variant, NMD_transcript_variant			ENSP00000493932
MYO3A	ENST00000642197.1 linkuse as main transcript	n.1257+12A>G	intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.474

AC:

71960

AN:

151702

Hom.:

17820

Cov.:

show subpopulations

Gnomad AFR

AF:

0.359

Gnomad AMI

AF:

0.428

Gnomad AMR

AF:

0.409

Gnomad ASJ

AF:

0.534

Gnomad EAS

AF:

0.271

Gnomad SAS

AF:

0.494

Gnomad FIN

AF:

0.578

Gnomad MID

AF:

0.608

Gnomad NFE

AF:

0.554

Gnomad OTH

AF:

0.477

GnomAD3 exomes

AF:

0.477

AC:

118721

AN:

248664

Hom.:

30013

AF XY:

0.489

AC XY:

65680

AN XY:

134450

show subpopulations

Gnomad AFR exome

AF:

0.352

Gnomad AMR exome

AF:

0.319

Gnomad ASJ exome

AF:

0.527

Gnomad EAS exome

AF:

0.271

Gnomad SAS exome

AF:

0.481

Gnomad FIN exome

AF:

0.578

Gnomad NFE exome

AF:

0.551

Gnomad OTH exome

AF:

0.503

GnomAD4 exome

AF:

0.526

AC:

732951

AN:

1394376

Hom.:

196863

Cov.:

AF XY:

0.526

AC XY:

366922

AN XY:

697350

show subpopulations

Gnomad4 AFR exome

AF:

0.357

Gnomad4 AMR exome

AF:

0.331

Gnomad4 ASJ exome

AF:

0.521

Gnomad4 EAS exome

AF:

0.262

Gnomad4 SAS exome

AF:

0.482

Gnomad4 FIN exome

AF:

0.575

Gnomad4 NFE exome

AF:

0.550

Gnomad4 OTH exome

AF:

0.514

GnomAD4 genome

AF:

0.474

AC:

71978

AN:

151820

Hom.:

17825

Cov.:

AF XY:

0.474

AC XY:

35153

AN XY:

74198

show subpopulations

Gnomad4 AFR

AF:

0.359

Gnomad4 AMR

AF:

0.409

Gnomad4 ASJ

AF:

0.534

Gnomad4 EAS

AF:

0.271

Gnomad4 SAS

AF:

0.493

Gnomad4 FIN

AF:

0.578

Gnomad4 NFE

AF:

0.554

Gnomad4 OTH

AF:

0.477

Alfa

AF:

0.518

Hom.:

3734

Bravo

AF:

0.451

Asia WGS

AF:

0.398

AC:

1384

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 20, 2012	1053+12A>G 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 46.6% (3270/7020) of European American chromoso mes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs .washington.edu/EVS; dbSNP rs3824697). -

not provided

Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 22, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 22, 2024	- -

Autosomal recessive nonsyndromic hearing loss 30

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.84

CADD

Benign

0.89

DANN

Benign

0.44

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over