rs34204285

Positions:

• chr10-26193228-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_017433.5(MYO3A):​c.4462A>G​(p.Lys1488Glu) variant causes a missense change. The variant allele was found at a frequency of 0.00144 in 1,614,002 control chromosomes in the GnomAD database, including 31 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0019 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (26 hom.)
• Consequence: MYO3A NM_017433.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 3.73

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 (MetaRNN=0.0026059747).
• BP6: Variant 10-26193228-A-G is Benign according to our data. Variant chr10-26193228-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 45815.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-26193228-A-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00187 (285/152302) while in subpopulation EAS AF= 0.0443 (230/5188). AF 95% confidence interval is 0.0396. There are 5 homozygotes in gnomad4. There are 166 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 5 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYO3A	NM_017433.5	c.4462A>G	p.Lys1488Glu	missense_variant	32/35	ENST00000642920.2	NP_059129.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYO3A	ENST00000642920.2	c.4462A>G	p.Lys1488Glu	missense_variant	32/35		NM_017433.5	ENSP00000495965.1
MYO3A	ENST00000543632.5	c.1777-18615A>G		intron_variant		1		ENSP00000445909.1
MYO3A	ENST00000647478.1	n.*1417A>G		non_coding_transcript_exon_variant	28/30			ENSP00000493932.1
MYO3A	ENST00000647478.1	n.*1417A>G		3_prime_UTR_variant	28/30			ENSP00000493932.1

Frequencies

GnomAD3 genomes AF: 0.00188 AC: 286 AN: 152184 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.0444

Gnomad SAS AF: 0.00395

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00392 AC: 984 AN: 251318 Hom.: 14 AF XY: 0.00377 AC XY: 512 AN XY: 135842

Gnomad AFR exome AF: 0.000370

Gnomad AMR exome AF: 0.000405

Gnomad ASJ exome AF: 0.000397

Gnomad EAS exome AF: 0.0469

Gnomad SAS exome AF: 0.00209

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000185

Gnomad OTH exome AF: 0.00212

GnomAD4 exome AF: 0.00139 AC: 2037 AN: 1461700 Hom.: 26 Cov.: 31 AF XY: 0.00143 AC XY: 1039 AN XY: 727164

Gnomad4 AFR exome AF: 0.000149

Gnomad4 AMR exome AF: 0.000470

Gnomad4 ASJ exome AF: 0.000383

Gnomad4 EAS exome AF: 0.0371

Gnomad4 SAS exome AF: 0.00204

Gnomad4 FIN exome AF: 0.0000374

Gnomad4 NFE exome AF: 0.000122

Gnomad4 OTH exome AF: 0.00346

GnomAD4 genome AF: 0.00187 AC: 285 AN: 152302 Hom.: 5 Cov.: 32 AF XY: 0.00223 AC XY: 166 AN XY: 74472

Gnomad4 AFR AF: 0.000168

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.0443

Gnomad4 SAS AF: 0.00395

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000250

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00199 Hom.: 10

Bravo AF: 0.00252

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00378 AC: 459

Asia WGS AF: 0.0240 AC: 84 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000119

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 06, 2024	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 14, 2018	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	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 14, 2023	- -
Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Nov 29, 2012

This variant was identified in 19/394 Asian control chromosomes. -

MYO3A-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 22, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.079	T;T
Eigen	Benign	0.082
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.69	.;T
MetaRNN	Benign	0.0026	T;T
MetaSVM	Benign	-0.69	T
MutationAssessor	Uncertain	2.3	M;M
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.70	.;N
REVEL	Uncertain	0.33
Sift	Uncertain	0.016	.;D
Sift4G	Benign	0.64	.;T
Polyphen		0.17	B;B
Vest4		0.43
MVP		0.72
MPC		0.14
ClinPred		0.024	T
GERP RS		5.7
Varity_R		0.18
gMVP		0.23

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: rs34204285; hg19: chr10-26482157; COSMIC: COSV56322765;