rs35575696

Positions:

• chr10-26174123-C-A

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 2P and 13B. PM5 BP4_Strong BP6 BS1 BS2

The NM_017433.5(MYO3A):​c.3859C>A​(p.Pro1287Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0107 in 1,614,124 control chromosomes in the GnomAD database, including 118 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P1287H) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.0081 (8 hom., cov: 33)
  • Exomes 𝑓: 0.011 (110 hom.)
• Consequence: MYO3A NM_017433.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 0.461

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 -11 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr10-26174124-C-A is described in Lovd as [Likely_pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.0032796562).
• BP6: Variant 10-26174123-C-A is Benign according to our data. Variant chr10-26174123-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 45810.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=5}. Variant chr10-26174123-C-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00814 (1240/152246) while in subpopulation NFE AF= 0.0115 (783/68012). AF 95% confidence interval is 0.0108. There are 8 homozygotes in gnomad4. There are 615 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 8 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYO3A	NM_017433.5	c.3859C>A	p.Pro1287Thr	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.3859C>A	p.Pro1287Thr	missense_variant	30/35		NM_017433.5	ENSP00000495965.1
MYO3A	ENST00000543632.5	c.1777-37720C>A		intron_variant		1		ENSP00000445909.1
MYO3A	ENST00000647478.1	n.*1393+3584C>A		intron_variant				ENSP00000493932.1

Frequencies

GnomAD3 genomes AF: 0.00816 AC: 1241 AN: 152128 Hom.: 8 Cov.: 33

Gnomad AFR AF: 0.00193

Gnomad AMI AF: 0.0395

Gnomad AMR AF: 0.00262

Gnomad ASJ AF: 0.0190

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0114

Gnomad FIN AF: 0.0164

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0115

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00929 AC: 2332 AN: 251140 Hom.: 17 AF XY: 0.0101 AC XY: 1371 AN XY: 135780

Gnomad AFR exome AF: 0.00142

Gnomad AMR exome AF: 0.00266

Gnomad ASJ exome AF: 0.0163

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.0140

Gnomad FIN exome AF: 0.0172

Gnomad NFE exome AF: 0.0106

Gnomad OTH exome AF: 0.00801

GnomAD4 exome AF: 0.0109 AC: 15993 AN: 1461878 Hom.: 110 Cov.: 73 AF XY: 0.0111 AC XY: 8102 AN XY: 727232

Gnomad4 AFR exome AF: 0.00128

Gnomad4 AMR exome AF: 0.00279

Gnomad4 ASJ exome AF: 0.0160

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0152

Gnomad4 FIN exome AF: 0.0159

Gnomad4 NFE exome AF: 0.0113

Gnomad4 OTH exome AF: 0.0102

GnomAD4 genome AF: 0.00814 AC: 1240 AN: 152246 Hom.: 8 Cov.: 33 AF XY: 0.00826 AC XY: 615 AN XY: 74422

Gnomad4 AFR AF: 0.00193

Gnomad4 AMR AF: 0.00261

Gnomad4 ASJ AF: 0.0190

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0112

Gnomad4 FIN AF: 0.0164

Gnomad4 NFE AF: 0.0115

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.0106 Hom.: 18

Bravo AF: 0.00677

TwinsUK AF: 0.00944 AC: 35

ALSPAC AF: 0.0104 AC: 40

ESP6500AA AF: 0.00182 AC: 8

ESP6500EA AF: 0.0110 AC: 95

ExAC AF: 0.00984 AC: 1195

Asia WGS AF: 0.00318 AC: 11 AN: 3478

EpiCase AF: 0.0106

EpiControl AF: 0.00966

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	MYO3A: BP4, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 03, 2018	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 07, 2012	Pro1287Thr in Exon 30 of MYO3A: This variant is not expected to have clinical si gnificance because it has been identified in 1.0% (72/7020) of European American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS; dbSNP rs35575696). -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 22, 2020	- -

Autosomal recessive nonsyndromic hearing loss 30 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	14
DANN	Benign	0.22
DEOGEN2	Benign	0.071	T;T
Eigen	Benign	-0.82
Eigen_PC	Benign	-0.82
FATHMM_MKL	Benign	0.25	N
LIST_S2	Benign	0.66	.;T
MetaRNN	Benign	0.0033	T;T
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	1.1	L;L
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.97	.;N
REVEL	Benign	0.12
Sift	Benign	0.12	.;T
Sift4G	Benign	0.26	.;T
Polyphen		0.017	B;B
Vest4		0.067
MVP		0.62
MPC		0.097
ClinPred		0.0019	T
GERP RS		1.8
Varity_R		0.080
gMVP		0.13

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: rs35575696; hg19: chr10-26463052;