10-26174514-C-T

Position:

• chr10-26174514-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_017433.5(MYO3A):​c.4250C>T​(p.Thr1417Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.012 in 1,613,830 control chromosomes in the GnomAD database, including 180 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 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 0.0075 (9 hom., cov: 32)
  • Exomes 𝑓: 0.012 (171 hom.)
• Consequence: MYO3A NM_017433.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 0.133

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 Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005092174).
• BP6: Variant 10-26174514-C-T is Benign according to our data. Variant chr10-26174514-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 45813.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=5}. Variant chr10-26174514-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00747 (1137/152236) while in subpopulation NFE AF= 0.013 (882/68016). AF 95% confidence interval is 0.0123. There are 9 homozygotes in gnomad4. There are 490 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 9 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYO3A	NM_017433.5	c.4250C>T	p.Thr1417Ile	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.4250C>T	p.Thr1417Ile	missense_variant	30/35		NM_017433.5	ENSP00000495965.1
MYO3A	ENST00000543632.5	c.1777-37329C>T		intron_variant		1		ENSP00000445909.1
MYO3A	ENST00000647478.1	n.*1393+3975C>T		intron_variant				ENSP00000493932.1

Frequencies

GnomAD3 genomes AF: 0.00748 AC: 1138 AN: 152118 Hom.: 9 Cov.: 32

Gnomad AFR AF: 0.00256

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00550

Gnomad ASJ AF: 0.00605

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00311

Gnomad FIN AF: 0.00160

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0130

Gnomad OTH AF: 0.00527

GnomAD3 exomes AF: 0.00748 AC: 1868 AN: 249594 Hom.: 12 AF XY: 0.00750 AC XY: 1015 AN XY: 135366

Gnomad AFR exome AF: 0.00198

Gnomad AMR exome AF: 0.00325

Gnomad ASJ exome AF: 0.00588

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00180

Gnomad FIN exome AF: 0.00189

Gnomad NFE exome AF: 0.0135

Gnomad OTH exome AF: 0.00855

GnomAD4 exome AF: 0.0125 AC: 18266 AN: 1461594 Hom.: 171 Cov.: 35 AF XY: 0.0123 AC XY: 8932 AN XY: 727066

Gnomad4 AFR exome AF: 0.00200

Gnomad4 AMR exome AF: 0.00340

Gnomad4 ASJ exome AF: 0.00655

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00237

Gnomad4 FIN exome AF: 0.00311

Gnomad4 NFE exome AF: 0.0152

Gnomad4 OTH exome AF: 0.00929

GnomAD4 genome AF: 0.00747 AC: 1137 AN: 152236 Hom.: 9 Cov.: 32 AF XY: 0.00658 AC XY: 490 AN XY: 74458

Gnomad4 AFR AF: 0.00255

Gnomad4 AMR AF: 0.00549

Gnomad4 ASJ AF: 0.00605

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00290

Gnomad4 FIN AF: 0.00160

Gnomad4 NFE AF: 0.0130

Gnomad4 OTH AF: 0.00521

Alfa AF: 0.0119 Hom.: 23

Bravo AF: 0.00776

TwinsUK AF: 0.0151 AC: 56

ALSPAC AF: 0.0150 AC: 58

ESP6500AA AF: 0.00318 AC: 14

ESP6500EA AF: 0.0147 AC: 126

ExAC AF: 0.00772 AC: 937

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.0129

EpiControl AF: 0.0125

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 24, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 12, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 19, 2024	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2023	MYO3A: BP4, BS1, BS2 -

Autosomal recessive nonsyndromic hearing loss 30 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

May 07, 2012

Thr1417Ile in Exon 30 of MYO3A: This variant is not expected to have clinical si gnificance because it has been identified in 1.5% (105/7018) of European America n chromosomes from a broad population by the NHLBI Exome Sequencing Project (htt p://evs.gs.washington.edu/EVS; dbSNP rs34151474). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	0.56
DANN	Benign	0.23
DEOGEN2	Benign	0.070	T;T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.026	N
LIST_S2	Benign	0.47	.;T
MetaRNN	Benign	0.0051	T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-0.60	N;N
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-0.49	.;N
REVEL	Benign	0.17
Sift	Benign	0.41	.;T
Sift4G	Benign	0.21	.;T
Polyphen		0.0	B;B
Vest4		0.025
MVP		0.43
MPC		0.065
ClinPred		0.00078	T
GERP RS		0.97
Varity_R		0.064
gMVP		0.023

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: rs34151474; hg19: chr10-26463443;