rs12573019

Variant names:

• chr10-26025376-G-A
• rs12573019
• NM_017433.5:c.798-1001G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_017433.5(MYO3A):​c.798-1001G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.126 in 150,428 control chromosomes in the GnomAD database, including 1,625 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.13 (1625 hom., cov: 31)
• Consequence: MYO3A NM_017433.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.53
• Publications: 3 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), PanelApp Australia, 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.347 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYO3A	NM_017433.5	c.798-1001G>A		intron_variant	Intron 9 of 34	ENST00000642920.2	NP_059129.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYO3A	ENST00000642920.2	c.798-1001G>A		intron_variant	Intron 9 of 34		NM_017433.5	ENSP00000495965.1
MYO3A	ENST00000543632.5	c.798-1001G>A		intron_variant	Intron 8 of 16	1		ENSP00000445909.1
MYO3A	ENST00000642197.1	n.1002-1001G>A		intron_variant	Intron 9 of 26
MYO3A	ENST00000647478.1	n.798-1001G>A		intron_variant	Intron 8 of 29			ENSP00000493932.1

Frequencies

GnomAD3 genomes AF: 0.126 AC: 18875 AN: 150310 Hom.: 1620 Cov.: 31

Gnomad AFR AF: 0.0282

Gnomad AMI AF: 0.100

Gnomad AMR AF: 0.184

Gnomad ASJ AF: 0.130

Gnomad EAS AF: 0.361

Gnomad SAS AF: 0.161

Gnomad FIN AF: 0.198

Gnomad MID AF: 0.144

Gnomad NFE AF: 0.140

Gnomad OTH AF: 0.133

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.126 AC: 18881 AN: 150428 Hom.: 1625 Cov.: 31 AF XY: 0.131 AC XY: 9644 AN XY: 73398

African (AFR) AF: 0.0281 AC: 1148 AN: 40800

American (AMR) AF: 0.184 AC: 2780 AN: 15100

Ashkenazi Jewish (ASJ) AF: 0.130 AC: 449 AN: 3462

East Asian (EAS) AF: 0.361 AC: 1846 AN: 5116

South Asian (SAS) AF: 0.162 AC: 768 AN: 4732

European-Finnish (FIN) AF: 0.198 AC: 2018 AN: 10194

Middle Eastern (MID) AF: 0.142 AC: 41 AN: 288

European-Non Finnish (NFE) AF: 0.140 AC: 9462 AN: 67732

Other (OTH) AF: 0.133 AC: 278 AN: 2094

Alfa AF: 0.135 Hom.: 2584

Bravo AF: 0.123

Asia WGS AF: 0.239 AC: 831 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	0.037
DANN	Benign	0.49
PhyloP100		-1.5
Mutation Taster		=100/0	polymorphism (auto)

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

dbSNP: rs12573019; hg19: chr10-26314305;