10-25952015-C-A

Variant names:

• chr10-25952015-C-A
• rs17450092
• NM_017433.5:c.-17-79C>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_017433.5(MYO3A):​c.-17-79C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000112 in 891,880 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 32)
  • Exomes 𝑓: 0.0000011 (0 hom.)
• Consequence: MYO3A NM_017433.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.150
• 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):

• nonsyndromic genetic hearing loss

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• autosomal recessive nonsyndromic hearing loss 30

  Inheritance: SD, AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, PanelApp Australia, Labcorp Genetics (formerly Invitae)
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).

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.-17-79C>A		intron	N/A	NP_059129.3
	MYO3A	NM_001368265.1		c.-17-79C>A		intron	N/A	NP_001355194.1	Q8NEV4-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYO3A	ENST00000642920.2	MANE Select	c.-17-79C>A		intron	N/A	ENSP00000495965.1	Q8NEV4-1
	MYO3A	ENST00000543632.5	TSL:1	c.-17-79C>A		intron	N/A	ENSP00000445909.1	F5H0U9
	MYO3A	ENST00000376302.5	TSL:1	c.-17-79C>A		intron	N/A	ENSP00000365479.1	Q8NEV4-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000112 AC: 1 AN: 891880 Hom.: 0 AF XY: 0.00000219 AC XY: 1 AN XY: 457060

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 20996

American (AMR) AF: 0.00 AC: 0 AN: 33572

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20980

East Asian (EAS) AF: 0.00 AC: 0 AN: 34500

South Asian (SAS) AF: 0.0000148 AC: 1 AN: 67454

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48660

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2988

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 622280

Other (OTH) AF: 0.00 AC: 0 AN: 40450

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.31
DANN	Benign	0.59
PhyloP100		-0.15

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: rs17450092; hg19: chr10-26240944;