rs3817420

Positions:

• chr10-26068819-G-A

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.1105G>A​(p.Val369Ile) variant causes a missense change. The variant allele was found at a frequency of 0.686 in 1,586,116 control chromosomes in the GnomAD database, including 375,414 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.69 (36541 hom., cov: 33)
  • Exomes 𝑓: 0.68 (338873 hom.)
• Consequence: MYO3A NM_017433.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 4.23

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]

MYO3A (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.2514962E-5).
• BP6: Variant 10-26068819-G-A is Benign according to our data. Variant chr10-26068819-G-A is described in ClinVar as [Benign]. Clinvar id is 45797.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-26068819-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.698 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYO3A	NM_017433.5	c.1105G>A	p.Val369Ile	missense_variant	12/35	ENST00000642920.2	NP_059129.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYO3A	ENST00000642920.2	c.1105G>A	p.Val369Ile	missense_variant	12/35		NM_017433.5	ENSP00000495965.1
MYO3A	ENST00000543632.5	c.1105G>A	p.Val369Ile	missense_variant	11/17	1		ENSP00000445909.1
MYO3A	ENST00000642197.1	n.1309G>A		non_coding_transcript_exon_variant	12/27
MYO3A	ENST00000647478.1	n.1105G>A		non_coding_transcript_exon_variant	11/30			ENSP00000493932.1

Frequencies

GnomAD3 genomes AF: 0.692 AC: 105006 AN: 151690 Hom.: 36509 Cov.: 33

Gnomad AFR AF: 0.704

Gnomad AMI AF: 0.532

Gnomad AMR AF: 0.634

Gnomad ASJ AF: 0.669

Gnomad EAS AF: 0.622

Gnomad SAS AF: 0.654

Gnomad FIN AF: 0.773

Gnomad MID AF: 0.771

Gnomad NFE AF: 0.697

Gnomad OTH AF: 0.690

GnomAD3 exomes AF: 0.677 AC: 169753 AN: 250642 Hom.: 57906 AF XY: 0.678 AC XY: 91870 AN XY: 135486

Gnomad AFR exome AF: 0.698

Gnomad AMR exome AF: 0.622

Gnomad ASJ exome AF: 0.670

Gnomad EAS exome AF: 0.618

Gnomad SAS exome AF: 0.631

Gnomad FIN exome AF: 0.771

Gnomad NFE exome AF: 0.696

Gnomad OTH exome AF: 0.679

GnomAD4 exome AF: 0.685 AC: 982490 AN: 1434310 Hom.: 338873 Cov.: 35 AF XY: 0.684 AC XY: 488683 AN XY: 714842

Gnomad4 AFR exome AF: 0.706

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: 0.690

Gnomad4 OTH exome AF: 0.681

GnomAD4 genome AF: 0.692 AC: 105090 AN: 151806 Hom.: 36541 Cov.: 33 AF XY: 0.694 AC XY: 51496 AN XY: 74160

Gnomad4 AFR AF: 0.705

Gnomad4 AMR AF: 0.634

Gnomad4 ASJ AF: 0.669

Gnomad4 EAS AF: 0.622

Gnomad4 SAS AF: 0.654

Gnomad4 FIN AF: 0.773

Gnomad4 NFE AF: 0.697

Gnomad4 OTH AF: 0.689

Alfa AF: 0.689 Hom.: 56400

Bravo AF: 0.681

ESP6500AA AF: 0.682 AC: 3004

ESP6500EA AF: 0.659 AC: 5668

ExAC AF: 0.679 AC: 82486

Asia WGS AF: 0.654 AC: 2272 AN: 3476

EpiCase AF: 0.692

EpiControl AF: 0.696

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

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. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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	May 07, 2012	Val369Ile in Exon 12 of MYO3A: This variant is not expected to have clinical sig nificance because it has been identified in 34.8% (2443/7020) of European Americ an chromosomes from a broad population by the NHLBI Exome Sequencing Project (ht tp://evs.gs.washington.edu/EVS; dbSNP rs3817420). -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

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	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.059
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	14
DANN	Uncertain	0.98
DEOGEN2	Benign	0.25	T;T;T
Eigen	Benign	-0.64
Eigen_PC	Benign	-0.45
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.45	.;T;T
MetaRNN	Benign	0.000013	T;T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	0.26	N;N;.
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.66	.;N;N
REVEL	Benign	0.21
Sift	Benign	0.30	.;T;T
Sift4G	Benign	0.12	.;T;T
Polyphen		0.0010	B;B;B
Vest4		0.13, 0.040
MPC		0.052
ClinPred		0.013	T
GERP RS		3.2
Varity_R		0.053
gMVP		0.54

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: rs3817420; hg19: chr10-26357748; COSMIC: COSV56318367;