rs77562287

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PP3_ModerateBP6BS1

The NM_017433.5(MYO3A):c.1275G>A(p.Gln425=) variant causes a splice region, synonymous change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000256 in 1,605,276 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/2 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0014 ( 1 hom., cov: 33)

Exomes 𝑓: 0.00014 ( 3 hom. )

Consequence

MYO3A
NM_017433.5 splice_region, synonymous

Scores

Splicing: ADA: 0.9999

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:4

Conservation

PhyloP100: 7.77

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. No scorers claiming Benign.

BP6

Variant 10-26070215-G-A is Benign according to our data. Variant chr10-26070215-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 178463.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=4}. Variant chr10-26070215-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00137 (208/152050) while in subpopulation AFR AF= 0.00486 (202/41528). AF 95% confidence interval is 0.00432. There are 1 homozygotes in gnomad4. There are 93 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYO3A	NM_017433.5 linkuse as main transcript	c.1275G>A	p.Gln425=	splice_region_variant, synonymous_variant	13/35	ENST00000642920.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYO3A	ENST00000642920.2 linkuse as main transcript	c.1275G>A	p.Gln425=	splice_region_variant, synonymous_variant	13/35		NM_017433.5	P1	Q8NEV4-1
MYO3A	ENST00000543632.5 linkuse as main transcript	c.1275G>A	p.Gln425=	splice_region_variant, synonymous_variant	12/17	1
MYO3A	ENST00000642197.1 linkuse as main transcript	n.1479G>A		splice_region_variant, non_coding_transcript_exon_variant	13/27
MYO3A	ENST00000647478.1 linkuse as main transcript	c.1275G>A	p.Gln425=	splice_region_variant, synonymous_variant, NMD_transcript_variant	12/30

Frequencies

GnomAD3 genomes

AF:

0.00136

AC:

207

AN:

151934

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00485

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000393

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000367

AC:

AN:

250774

Hom.:

AF XY:

0.000221

AC XY:

AN XY:

135586

show subpopulations

Gnomad AFR exome

AF:

0.00537

Gnomad AMR exome

AF:

0.0000869

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000328

GnomAD4 exome

AF:

0.000140

AC:

203

AN:

1453226

Hom.:

Cov.:

AF XY:

0.000111

AC XY:

AN XY:

723582

show subpopulations

Gnomad4 AFR exome

AF:

0.00517

Gnomad4 AMR exome

AF:

0.000179

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.05e-7

Gnomad4 OTH exome

AF:

0.000350

GnomAD4 genome

AF:

0.00137

AC:

208

AN:

152050

Hom.:

Cov.:

AF XY:

0.00125

AC XY:

AN XY:

74316

show subpopulations

Gnomad4 AFR

AF:

0.00486

Gnomad4 AMR

AF:

0.000393

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000333

Hom.:

Bravo

AF:

0.00165

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Nov 29, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 25, 2021	In-silico analysis, which includes splice predictors and evolutionary conservation, is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 27535533) -

not specified

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 13, 2013	Gln425Gln in Exon 13 of MYO3A: This variant is not expected to have clinical sig nificance because it does not alter an amino acid residue, and has been identifi ed in 0.4% (17/4406) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS; dbSNP rs77 562287). -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 18, 2017	- -

MYO3A-related condition

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 26, 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

BayesDel_noAF

Benign

-0.19

Cadd

Benign

Dann

Benign

0.95

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.95

SpliceAI score (max)

0.65

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.65

Position offset: 0

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over