10-26067063-A-G

Position:

• chr10-26067063-A-G

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.1042A>G​(p.Ile348Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.686 in 1,603,116 control chromosomes in the GnomAD database, including 378,441 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.69 (35977 hom., cov: 32)
  • Exomes 𝑓: 0.69 (342464 hom.)
• Consequence: MYO3A NM_017433.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 2.06

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.3441309E-6).
• BP6: Variant 10-26067063-A-G is Benign according to our data. Variant chr10-26067063-A-G is described in ClinVar as [Benign]. Clinvar id is 45792.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-26067063-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.692 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYO3A	NM_017433.5	c.1042A>G	p.Ile348Val	missense_variant	11/35	ENST00000642920.2	NP_059129.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYO3A	ENST00000642920.2	c.1042A>G	p.Ile348Val	missense_variant	11/35		NM_017433.5	ENSP00000495965.1
MYO3A	ENST00000543632.5	c.1042A>G	p.Ile348Val	missense_variant	10/17	1		ENSP00000445909.1
MYO3A	ENST00000642197.1	n.1246A>G		non_coding_transcript_exon_variant	11/27
MYO3A	ENST00000647478.1	n.1042A>G		non_coding_transcript_exon_variant	10/30			ENSP00000493932.1

Frequencies

GnomAD3 genomes AF: 0.686 AC: 104265 AN: 151950 Hom.: 35943 Cov.: 32

Gnomad AFR AF: 0.682

Gnomad AMI AF: 0.532

Gnomad AMR AF: 0.631

Gnomad ASJ AF: 0.670

Gnomad EAS AF: 0.623

Gnomad SAS AF: 0.655

Gnomad FIN AF: 0.774

Gnomad MID AF: 0.772

Gnomad NFE AF: 0.697

Gnomad OTH AF: 0.686

GnomAD3 exomes AF: 0.676 AC: 169513 AN: 250758 Hom.: 57719 AF XY: 0.677 AC XY: 91760 AN XY: 135540

Gnomad AFR exome AF: 0.675

Gnomad AMR exome AF: 0.622

Gnomad ASJ exome AF: 0.670

Gnomad EAS exome AF: 0.619

Gnomad SAS exome AF: 0.631

Gnomad FIN exome AF: 0.772

Gnomad NFE exome AF: 0.696

Gnomad OTH exome AF: 0.678

GnomAD4 exome AF: 0.685 AC: 994667 AN: 1451048 Hom.: 342464 Cov.: 33 AF XY: 0.684 AC XY: 494153 AN XY: 722420

Gnomad4 AFR exome AF: 0.685

Gnomad4 AMR exome AF: 0.622

Gnomad4 ASJ exome AF: 0.666

Gnomad4 EAS exome AF: 0.620

Gnomad4 SAS exome AF: 0.632

Gnomad4 FIN exome AF: 0.767

Gnomad4 NFE exome AF: 0.691

Gnomad4 OTH exome AF: 0.681

GnomAD4 genome AF: 0.686 AC: 104353 AN: 152068 Hom.: 35977 Cov.: 32 AF XY: 0.688 AC XY: 51179 AN XY: 74342

Gnomad4 AFR AF: 0.683

Gnomad4 AMR AF: 0.631

Gnomad4 ASJ AF: 0.670

Gnomad4 EAS AF: 0.623

Gnomad4 SAS AF: 0.656

Gnomad4 FIN AF: 0.774

Gnomad4 NFE AF: 0.697

Gnomad4 OTH AF: 0.685

Alfa AF: 0.687 Hom.: 88899

Bravo AF: 0.673

ESP6500AA AF: 0.680 AC: 2996

ESP6500EA AF: 0.684 AC: 5881

ExAC AF: 0.678 AC: 82338

Asia WGS AF: 0.656 AC: 2281 AN: 3478

EpiCase AF: 0.692

EpiControl AF: 0.697

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 07, 2012	Ile348Val in Exon 11 of MYO3A: This variant is not expected to have clinical sig nificance because it has been identified in 32.5% (1216/3738) of African America n chromosomes from a broad population by the NHLBI Exome Sequencing Project (htt p://evs.gs.washington.edu/EVS; dbSNP rs3824699). -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 09, 2017	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. -

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	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.059
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	7.8
DANN	Benign	0.34
DEOGEN2	Benign	0.13	T;T;T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.75
FATHMM_MKL	Benign	0.016	N
LIST_S2	Benign	0.27	.;T;T
MetaRNN	Benign	0.0000013	T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	-0.83	N;N;.
PrimateAI	Benign	0.35	T
PROVEAN	Benign	0.52	.;N;N
REVEL	Benign	0.11
Sift	Benign	1.0	.;T;T
Sift4G	Benign	0.78	.;T;T
Polyphen		0.0	B;B;B
Vest4		0.065, 0.034
MPC		0.053
ClinPred		0.00051	T
GERP RS		2.7
Varity_R		0.029
gMVP		0.29

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: rs3824699; hg19: chr10-26355992; COSMIC: COSV56319868;