rs140301218

chr10-25997174-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 3P and 7B. PM2 PP3 BP4_Moderate BP6 BS1

The NM_017433.5(MYO3A):c.424C>T(p.His142Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000217 in 1,612,892 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H142Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0012 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00012 (0 hom.)
• Consequence: MYO3A NM_017433.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 7.71

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 Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Multiple lines of computational evidence support a deleterious effect 8: AlphaMissense, BayesDel_noAF, Cadd, Eigen, MutationAssessor, phyloP100way_vertebrate, PROVEAN, REVEL [when FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.12456614).
• BP6: Variant 10-25997174-C-T is Benign according to our data. Variant chr10-25997174-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 504639.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00116 (177/152204) while in subpopulation AFR AF= 0.00359 (149/41538). AF 95% confidence interval is 0.00312. There are 0 homozygotes in gnomad4. There are 86 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	c.424C>T	p.His142Tyr	missense_variant	6/35	ENST00000642920.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYO3A	ENST00000642920.2	c.424C>T	p.His142Tyr	missense_variant	6/35		NM_017433.5	P1

Frequencies

GnomAD3 genomes AF: 0.00116 AC: 177 AN: 152086 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00360

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00138

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.000215 AC: 54 AN: 251036 Hom.: 0 AF XY: 0.000147 AC XY: 20 AN XY: 135664

Gnomad AFR exome AF: 0.00277

Gnomad AMR exome AF: 0.000202

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000118 AC: 173 AN: 1460688 Hom.: 0 Cov.: 30 AF XY: 0.0000963 AC XY: 70 AN XY: 726748

Gnomad4 AFR exome AF: 0.00407

Gnomad4 AMR exome AF: 0.000268

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.000282

GnomAD4 genome AF: 0.00116 AC: 177 AN: 152204 Hom.: 0 Cov.: 33 AF XY: 0.00116 AC XY: 86 AN XY: 74406

Gnomad4 AFR AF: 0.00359

Gnomad4 AMR AF: 0.00137

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.000160 Hom.: 0

Bravo AF: 0.00152

ESP6500AA AF: 0.00386 AC: 17

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000305 AC: 37

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Nov 29, 2021	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27535533, 33078831) -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Nov 28, 2023	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 30, 2012

His142Tyr in Exon 06 of MYO3A: This variant is not expected to have clinical sig nificance because it has been identified in 0.3% (13/3738) of African American c hromosomes from a broad population by the NHLBI Exome Sequencing Project (http:/ /evs.gs.washington.edu/EVS; dbSNP rs140301218). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Pathogenic	0.40
Cadd	Pathogenic	29
Dann	Uncertain	1.0
DEOGEN2	Benign	0.38	T;T;.;T
Eigen	Pathogenic	0.97
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Uncertain	0.22	D
MetaRNN	Benign	0.12	T;T;T;T
MetaSVM	Uncertain	0.69	D
MutationAssessor	Pathogenic	3.6	H;H;H;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.61	T
Polyphen		1.0	D;D;.;D
Vest4		0.98, 0.93, 0.96
MVP		0.96
MPC		0.41
ClinPred		0.16	T
GERP RS		5.4
Varity_R		0.94
gMVP		0.86

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: rs140301218; hg19: chr10-26286103;