rs3824699

Positions:

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_017433.5(MYO3A):c.1042A>C(p.Ile348Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,454,572 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I348V) has been classified as Benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

MYO3A
NM_017433.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.06

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.106227994).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYO3A	NM_017433.5 linkuse as main transcript	c.1042A>C	p.Ile348Leu	missense_variant	11/35	ENST00000642920.2	NP_059129.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYO3A	ENST00000642920.2 linkuse as main transcript	c.1042A>C	p.Ile348Leu	missense_variant	11/35		NM_017433.5	ENSP00000495965	P1	Q8NEV4-1
MYO3A	ENST00000543632.5 linkuse as main transcript	c.1042A>C	p.Ile348Leu	missense_variant	10/17	1		ENSP00000445909
MYO3A	ENST00000642197.1 linkuse as main transcript	n.1246A>C		non_coding_transcript_exon_variant	11/27
MYO3A	ENST00000647478.1 linkuse as main transcript	c.1042A>C	p.Ile348Leu	missense_variant, NMD_transcript_variant	10/30			ENSP00000493932

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000206

AC:

AN:

1454572

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

724062

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000271

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 26, 2021

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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with MYO3A-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces isoleucine with leucine at codon 348 of the MYO3A protein (p.Ile348Leu). The isoleucine residue is weakly conserved and there is a small physicochemical difference between isoleucine and leucine. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.087

BayesDel_addAF

Benign

-0.061

BayesDel_noAF

Benign

-0.33

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.21

T;T;T

Eigen

Benign

-0.68

Eigen_PC

Benign

-0.51

FATHMM_MKL

Uncertain

0.79

LIST_S2

Benign

0.65

.;T;T

M_CAP

Benign

0.041

MetaRNN

Benign

0.11

T;T;T

MetaSVM

Benign

-0.63

MutationAssessor

Benign

0.58

N;N;.

MutationTaster

Benign

1.0

P;P

PrimateAI

Benign

0.36

PROVEAN

Benign

-0.80

.;N;N

REVEL

Benign

0.14

Sift

Benign

0.11

.;T;T

Sift4G

Benign

0.68

.;T;T

Polyphen

0.0

B;B;B

Vest4

0.26, 0.23

MutPred

0.35

Gain of disorder (P = 0.0851);Gain of disorder (P = 0.0851);Gain of disorder (P = 0.0851);

MVP

0.64

MPC

0.061

ClinPred

0.14

GERP RS

2.7

Varity_R

0.14

gMVP

0.42

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over