rs200205050

Variant names:

• chr10-26128381-A-G
• rs200205050
• NM_017433.5:c.2115-10A>G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_017433.5(MYO3A):​c.2115-10A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000447 in 1,612,272 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000046 (0 hom.)
• Consequence: MYO3A NM_017433.5 intron
• Scores: Splicing: ADA: 0.9240
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 0.446

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. Scorers claiming Benign: dbscSNV1_ADA.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYO3A	NM_017433.5	c.2115-10A>G		intron_variant	Intron 19 of 34	ENST00000642920.2	NP_059129.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYO3A	ENST00000642920.2	c.2115-10A>G		intron_variant	Intron 19 of 34		NM_017433.5	ENSP00000495965.1
MYO3A	ENST00000543632.5	c.1776+31699A>G		intron_variant	Intron 16 of 16	1		ENSP00000445909.1
MYO3A	ENST00000642197.1	n.2319-10A>G		intron_variant	Intron 19 of 26
MYO3A	ENST00000647478.1	n.*110-10A>G		intron_variant	Intron 17 of 29			ENSP00000493932.1

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152186 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000558 AC: 14 AN: 250828 Hom.: 0 AF XY: 0.0000812 AC XY: 11 AN XY: 135548

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000706

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000459 AC: 67 AN: 1459968 Hom.: 0 Cov.: 31 AF XY: 0.0000606 AC XY: 44 AN XY: 726416

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000758

Gnomad4 SAS exome AF: 0.000151

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000396

Gnomad4 OTH exome AF: 0.0000829

GnomAD4 genome AF: 0.0000328 AC: 5 AN: 152304 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74464

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000868 Hom.: 0

Bravo AF: 0.0000189

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

May 16, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports a deleterious effect on splicing; Has not been previously published as pathogenic or benign to our knowledge -

Mar 04, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This sequence change falls in intron 19 of the MYO3A gene. It does not directly change the encoded amino acid sequence of the MYO3A protein. This variant is present in population databases (rs200205050, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with MYO3A-related conditions. ClinVar contains an entry for this variant (Variation ID: 228979). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. -

not specified Uncertain:1

Dec 31, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2115-10A>C variant in MYO3A has not been previously reported in individual s with hearing loss or in large population studies. This variant is located in t he 3' splice region. Computational tools do not suggest an impact to splicing. H owever, this information is not predictive enough to rule out pathogenicity. In summary, the clinical significance of the c.2115-10A>C variant is uncertain. -

Autosomal recessive nonsyndromic hearing loss 30 Uncertain:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	9.5
DANN	Benign	0.52

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.92
dbscSNV1_RF	Pathogenic	0.91
SpliceAI score (max)		0.95		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.67		Position offset: 1
DS_AL_spliceai		0.95		Position offset: 10

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs200205050; hg19: chr10-26417310;