rs3824698

Positions:

• chr10-26067085-C-T

Variant summary

Our verdict is Benign. Variant got -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

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]

ACMG classification

Verdict is Benign. Variant got -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 id is 45793.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-26067085-C-T 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	c.1053+11C>T		intron_variant		ENST00000642920.2	NP_059129.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYO3A	ENST00000642920.2	c.1053+11C>T		intron_variant			NM_017433.5	ENSP00000495965	P1
MYO3A	ENST00000543632.5	c.1053+11C>T		intron_variant		1		ENSP00000445909
MYO3A	ENST00000647478.1	c.1053+11C>T		intron_variant, NMD_transcript_variant				ENSP00000493932
MYO3A	ENST00000642197.1	n.1257+11C>T		intron_variant, non_coding_transcript_variant

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

GnomAD3 exomes AF: 0.477 AC: 118648 AN: 248680 Hom.: 30005 AF XY: 0.488 AC XY: 65645 AN XY: 134442

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 SAS exome AF: 0.481

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

Gnomad4 AFR exome AF: 0.358

Gnomad4 AMR exome AF: 0.329

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: 0.551

Gnomad4 OTH exome AF: 0.514

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

Gnomad4 AFR AF: 0.359

Gnomad4 AMR AF: 0.408

Gnomad4 ASJ AF: 0.535

Gnomad4 EAS AF: 0.272

Gnomad4 SAS AF: 0.493

Gnomad4 FIN AF: 0.579

Gnomad4 NFE AF: 0.554

Gnomad4 OTH AF: 0.477

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

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+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

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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. -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 22, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.27
DANN	Benign	0.55

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

Other links and lift over

dbSNP: rs3824698; hg19: chr10-26356014; COSMIC: COSV56348758;