10-25934301-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_017433.5(MYO3A):c.-132A>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0797 in 152,362 control chromosomes in the GnomAD database, including 597 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.080 (597 hom., cov: 32)
  • Exomes 𝑓: 0.11 (0 hom.)
• Consequence: MYO3A NM_017433.5 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.398

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BP6: Variant 10-25934301-A-G is Benign according to our data. Variant chr10-25934301-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 299639.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.135 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYO3A	NM_017433.5	c.-132A>G		5_prime_UTR_variant	1/35	ENST00000642920.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYO3A	ENST00000642920.2	c.-132A>G		5_prime_UTR_variant	1/35		NM_017433.5	P1
MYO3A	ENST00000376302.5	c.-132A>G		5_prime_UTR_variant	1/8	1
MYO3A	ENST00000642197.1	n.73A>G		non_coding_transcript_exon_variant	1/27

Frequencies

GnomAD3 genomes AF: 0.0795 AC: 12095 AN: 152062 Hom.: 593 Cov.: 32

Gnomad AFR AF: 0.138

Gnomad AMI AF: 0.148

Gnomad AMR AF: 0.0468

Gnomad ASJ AF: 0.0222

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.00642

Gnomad FIN AF: 0.0904

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0638

Gnomad OTH AF: 0.0621

GnomAD4 exome AF: 0.106 AC: 20 AN: 188 Hom.: 0 Cov.: 0 AF XY: 0.106 AC XY: 18 AN XY: 170

Gnomad4 AFR 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: 0.110

Gnomad4 OTH exome AF: 0.250

GnomAD4 genome AF: 0.0797 AC: 12125 AN: 152174 Hom.: 597 Cov.: 32 AF XY: 0.0793 AC XY: 5900 AN XY: 74412

Gnomad4 AFR AF: 0.138

Gnomad4 AMR AF: 0.0466

Gnomad4 ASJ AF: 0.0222

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.00642

Gnomad4 FIN AF: 0.0904

Gnomad4 NFE AF: 0.0638

Gnomad4 OTH AF: 0.0614

Alfa AF: 0.0656 Hom.: 104

Bravo AF: 0.0788

Asia WGS AF: 0.00895 AC: 32 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 30 Benign:1

Likely benign, 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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
Cadd	Benign	7.7
Dann	Benign	0.30

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs7073224; hg19: chr10-26223230;