rs193919333

Positions:

• chr10-26168729-T-G

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_017433.5(MYO3A):​c.3129T>G​(p.Tyr1043Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: MYO3A NM_017433.5 stop_gained
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 0.353

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 Pathogenic. Variant got 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 10-26168729-T-G is Pathogenic according to our data. Variant chr10-26168729-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 4014.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr10-26168729-T-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYO3A	NM_017433.5	c.3129T>G	p.Tyr1043Ter	stop_gained	28/35	ENST00000642920.2	NP_059129.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYO3A	ENST00000642920.2	c.3129T>G	p.Tyr1043Ter	stop_gained	28/35		NM_017433.5	ENSP00000495965	P1
MYO3A	ENST00000543632.5	c.1777-43114T>G		intron_variant		1		ENSP00000445909
MYO3A	ENST00000477691.2	n.355T>G		non_coding_transcript_exon_variant	2/2	2
MYO3A	ENST00000647478.1	c.*1124T>G		3_prime_UTR_variant, NMD_transcript_variant	26/30			ENSP00000493932

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 30 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Apr 01, 2011

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	36
DANN	Uncertain	0.99
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Uncertain	0.87	D
MutationTaster	Benign	1.0	A;A
Vest4		0.98
GERP RS		1.8

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs193919333; hg19: chr10-26457658;