rs184043065

Positions:

• chr10-26173802-G-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Strong BP6 BS2_Supporting

The NM_017433.5(MYO3A):​c.3538G>A​(p.Glu1180Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000981 in 1,614,116 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 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 0.00074 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0010 (2 hom.)
• Consequence: MYO3A NM_017433.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:2
• Conservation: PhyloP100: 3.21

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 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.021226734).
• BP6: Variant 10-26173802-G-A is Benign according to our data. Variant chr10-26173802-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 178468.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=6}. Variant chr10-26173802-G-A is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAdExome4 at 2 SD geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYO3A	NM_017433.5	c.3538G>A	p.Glu1180Lys	missense_variant	30/35	ENST00000642920.2	NP_059129.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYO3A	ENST00000642920.2	c.3538G>A	p.Glu1180Lys	missense_variant	30/35		NM_017433.5	ENSP00000495965.1
MYO3A	ENST00000543632.5	c.1777-38041G>A		intron_variant		1		ENSP00000445909.1
MYO3A	ENST00000647478.1	n.*1393+3263G>A		intron_variant				ENSP00000493932.1

Frequencies

GnomAD3 genomes AF: 0.000736 AC: 112 AN: 152180 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000338

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000523

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000565

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00115

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000609 AC: 153 AN: 251206 Hom.: 0 AF XY: 0.000611 AC XY: 83 AN XY: 135814

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.000202

Gnomad ASJ exome AF: 0.000993

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.000832

Gnomad NFE exome AF: 0.000951

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.00101 AC: 1472 AN: 1461818 Hom.: 2 Cov.: 32 AF XY: 0.000982 AC XY: 714 AN XY: 727200

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.000224

Gnomad4 ASJ exome AF: 0.000842

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.000693

Gnomad4 NFE exome AF: 0.00120

Gnomad4 OTH exome AF: 0.00106

GnomAD4 genome AF: 0.000735 AC: 112 AN: 152298 Hom.: 0 Cov.: 32 AF XY: 0.000564 AC XY: 42 AN XY: 74472

Gnomad4 AFR AF: 0.000337

Gnomad4 AMR AF: 0.000523

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.000565

Gnomad4 NFE AF: 0.00115

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00116 Hom.: 0

Bravo AF: 0.000688

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000698 AC: 6

ExAC AF: 0.000700 AC: 85

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00115

EpiControl AF: 0.000652

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	MYO3A: BP4, BS1:Supporting -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 22, 2023	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 1180 of the MYO3A protein (p.Glu1180Lys). This variant is present in population databases (rs184043065, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. 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: 178468). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt MYO3A protein function with a negative predictive value of 80%. 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 29, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	May 03, 2021	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Autosomal recessive nonsyndromic hearing loss 30 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	May 05, 2022	The MYO3A c.3538G>A; p.Glu1180Lys variant (rs184043065), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 178468). This variant is found in the non-Finnish European population with an allele frequency of 0.098% (126/129,020 alleles) in the Genome Aggregation Database. The glutamic acid at codon 1180 is weakly conserved, and computational analyses predict that this variant is neutral (REVEL: 0.131). Due to limited information, the clinical significance of the p.Glu1180Lys variant is uncertain at this time. -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 17, 2022

The c.3538G>A (p.E1180K) alteration is located in exon 30 (coding exon 28) of the MYO3A gene. This alteration results from a G to A substitution at nucleotide position 3538, causing the glutamic acid (E) at amino acid position 1180 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Feb 04, 2016

p.Glu1180Lys in exon 30 of MYO3A: This variant is not expected to have clinical significance because it has been identified in 0.2% (10/6614) of Finnish chromos omes and in 0.1% (69/66376) of European chromosomes by the Exome Aggregation Con sortium (ExAC, http://exac.broadinstitute.org; dbSNP rs184043065). In addition, the glutamine (Glu) residue at position 1180 is not conserved across species an d computational analyses (biochemical amino acid properties, AlignGVGD, PolyPhe n2, and SIFT) suggest that the Glu1180Lys variant may not impact the protein. Of note, horse has a lysine (Lys) at this position. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.075	T;T
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.48
FATHMM_MKL	Benign	0.71	D
LIST_S2	Benign	0.61	.;T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.021	T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.0	L;L
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.73	.;N
REVEL	Benign	0.13
Sift	Benign	0.087	.;T
Sift4G	Benign	0.21	.;T
Polyphen		0.0020	B;B
Vest4		0.17
MVP		0.74
MPC		0.068
ClinPred		0.020	T
GERP RS		3.4
Varity_R		0.044
gMVP		0.20

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: rs184043065; hg19: chr10-26462731; COSMIC: COSV99778705; COSMIC: COSV99778705;