rs147376000

chr10-26193231-A-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_017433.5(MYO3A):c.4465A>G(p.Ile1489Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00637 in 1,613,820 control chromosomes in the GnomAD database, including 49 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0052 (4 hom., cov: 31)
  • Exomes 𝑓: 0.0065 (45 hom.)
• Consequence: MYO3A NM_017433.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:7
• Conservation: PhyloP100: 0.314

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004360676).
• BP6: Variant 10-26193231-A-G is Benign according to our data. Variant chr10-26193231-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 45816.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Benign=5, Uncertain_significance=1}. Variant chr10-26193231-A-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00519 (790/152270) while in subpopulation NFE AF= 0.00626 (426/68024). AF 95% confidence interval is 0.00577. There are 4 homozygotes in gnomad4. There are 414 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 4 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYO3A	NM_017433.5	c.4465A>G	p.Ile1489Val	missense_variant	32/35	ENST00000642920.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYO3A	ENST00000642920.2	c.4465A>G	p.Ile1489Val	missense_variant	32/35		NM_017433.5	P1
MYO3A	ENST00000543632.5	c.1777-18612A>G		intron_variant		1
MYO3A	ENST00000647478.1	c.*1420A>G		3_prime_UTR_variant, NMD_transcript_variant	28/30

Frequencies

GnomAD3 genomes AF: 0.00519 AC: 790 AN: 152152 Hom.: 4 Cov.: 31

Gnomad AFR AF: 0.00130

Gnomad AMI AF: 0.00877

Gnomad AMR AF: 0.00236

Gnomad ASJ AF: 0.00375

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.0224

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00626

Gnomad OTH AF: 0.00478

GnomAD3 exomes AF: 0.00532 AC: 1337 AN: 251330 Hom.: 6 AF XY: 0.00544 AC XY: 739 AN XY: 135846

Gnomad AFR exome AF: 0.00129

Gnomad AMR exome AF: 0.00150

Gnomad ASJ exome AF: 0.00218

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00137

Gnomad FIN exome AF: 0.0188

Gnomad NFE exome AF: 0.00660

Gnomad OTH exome AF: 0.00700

GnomAD4 exome AF: 0.00650 AC: 9496 AN: 1461550 Hom.: 45 Cov.: 31 AF XY: 0.00639 AC XY: 4643 AN XY: 727086

Gnomad4 AFR exome AF: 0.000926

Gnomad4 AMR exome AF: 0.00192

Gnomad4 ASJ exome AF: 0.00249

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00154

Gnomad4 FIN exome AF: 0.0176

Gnomad4 NFE exome AF: 0.00715

Gnomad4 OTH exome AF: 0.00475

GnomAD4 genome AF: 0.00519 AC: 790 AN: 152270 Hom.: 4 Cov.: 31 AF XY: 0.00556 AC XY: 414 AN XY: 74456

Gnomad4 AFR AF: 0.00130

Gnomad4 AMR AF: 0.00235

Gnomad4 ASJ AF: 0.00375

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.0224

Gnomad4 NFE AF: 0.00626

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.00560 Hom.: 2

Bravo AF: 0.00414

TwinsUK AF: 0.00485 AC: 18

ALSPAC AF: 0.00675 AC: 26

ESP6500AA AF: 0.00159 AC: 7

ESP6500EA AF: 0.00581 AC: 50

ExAC AF: 0.00541 AC: 657

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00474

EpiControl AF: 0.00510

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:7

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 25, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 19, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	MYO3A: BP4, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jun 26, 2017	- -

Autosomal recessive nonsyndromic hearing loss 30 Uncertain:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 06, 2023	- -
Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 21, 2014	Ile1489Val in Exon 32 of MYO3A: This variant is not expected to have clinical si gnificance because it has been identified in 0.6% (50/8600) of European American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS; dbSNP rs147376000). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.43
Cadd	Benign	9.7
Dann	Benign	0.44
DEOGEN2	Benign	0.063	T;T
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.48
FATHMM_MKL	Benign	0.22	N
MetaRNN	Benign	0.0044	T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.9	M;M
MutationTaster	Benign	0.98	D;N
PrimateAI	Benign	0.45	T
Polyphen		0.023	B;B
Vest4		0.18
MVP		0.57
MPC		0.057
ClinPred		0.0079	T
GERP RS		2.0
Varity_R		0.042
gMVP		0.028

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: rs147376000; hg19: chr10-26482160; COSMIC: COSV56341352;