NM_017433.5:c.58dupA

Variant names:

• chr10-25952167-T-TA
• NM_017433.5:c.58dupA

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_017433.5(MYO3A):​c.58dupA​(p.Thr20AsnfsTer6) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MYO3A NM_017433.5 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 5.20
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• autosomal recessive nonsyndromic hearing loss 30

  Inheritance: AR, SD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• nonsyndromic genetic hearing loss

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• hearing loss, autosomal dominant 90

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 54 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 10-25952167-T-TA is Pathogenic according to our data. Variant chr10-25952167-T-TA is described in ClinVar as Pathogenic. ClinVar VariationId is 3697693.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017433.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYO3A	NM_017433.5	MANE Select	c.58dupA	p.Thr20AsnfsTer6	frameshift	Exon 3 of 35	NP_059129.3
	MYO3A	NM_001368265.1		c.58dupA	p.Thr20AsnfsTer6	frameshift	Exon 3 of 8	NP_001355194.1	Q8NEV4-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYO3A	ENST00000642920.2	MANE Select	c.58dupA	p.Thr20AsnfsTer6	frameshift	Exon 3 of 35	ENSP00000495965.1	Q8NEV4-1
	MYO3A	ENST00000543632.5	TSL:1	c.58dupA	p.Thr20AsnfsTer6	frameshift	Exon 2 of 17	ENSP00000445909.1	F5H0U9
	MYO3A	ENST00000376302.5	TSL:1	c.58dupA	p.Thr20AsnfsTer6	frameshift	Exon 3 of 8	ENSP00000365479.1	Q8NEV4-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		5.2

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

Other links and lift over

hg19: chr10-26241096;