rs146797033

Positions:

• chr10-26088343-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 2P and 15B. PM2 BP4_Moderate BP6_Very_Strong BP7 BS1

The NM_017433.5(MYO3A):​c.1500G>A​(p.Ala500Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000175 in 1,613,830 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0010 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000088 (0 hom.)
• Consequence: MYO3A NM_017433.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0380

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.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.39).
• BP6: Variant 10-26088343-G-A is Benign according to our data. Variant chr10-26088343-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 178464.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-26088343-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.038 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00102 (155/152278) while in subpopulation AFR AF= 0.00363 (151/41556). AF 95% confidence interval is 0.00316. There are 0 homozygotes in gnomad4. There are 70 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYO3A	NM_017433.5	c.1500G>A	p.Ala500Ala	synonymous_variant	15/35	ENST00000642920.2	NP_059129.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYO3A	ENST00000642920.2	c.1500G>A	p.Ala500Ala	synonymous_variant	15/35		NM_017433.5	ENSP00000495965.1
MYO3A	ENST00000543632.5	c.1500G>A	p.Ala500Ala	synonymous_variant	14/17	1		ENSP00000445909.1
MYO3A	ENST00000642197.1	n.1704G>A		non_coding_transcript_exon_variant	15/27
MYO3A	ENST00000647478.1	n.1500G>A		non_coding_transcript_exon_variant	14/30			ENSP00000493932.1

Frequencies

GnomAD3 genomes AF: 0.00102 AC: 155 AN: 152160 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00364

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000251 AC: 63 AN: 251316 Hom.: 0 AF XY: 0.000169 AC XY: 23 AN XY: 135832

Gnomad AFR exome AF: 0.00345

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.000327

GnomAD4 exome AF: 0.0000876 AC: 128 AN: 1461552 Hom.: 0 Cov.: 31 AF XY: 0.0000660 AC XY: 48 AN XY: 727074

Gnomad4 AFR exome AF: 0.00287

Gnomad4 AMR exome AF: 0.0000895

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000562

Gnomad4 NFE exome AF: 0.0000162

Gnomad4 OTH exome AF: 0.0000994

GnomAD4 genome AF: 0.00102 AC: 155 AN: 152278 Hom.: 0 Cov.: 32 AF XY: 0.000940 AC XY: 70 AN XY: 74456

Gnomad4 AFR AF: 0.00363

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000395 Hom.: 0

Bravo AF: 0.00111

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 30, 2012

Ala500Ala in Exon 15 of MYO3A: This variant is not expected to have clinical sig nificance because it does not alter an amino acid residue, is not located within the splice consensus sequence, and has been identified in 0.4% (15/3738) of Afr ican American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS; dbSNP rs146797033). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 11, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.39
CADD	Benign	11
DANN	Benign	0.60

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: rs146797033; hg19: chr10-26377272;