10-26174337-G-C

Variant names:

• chr10-26174337-G-C
• rs141903506
• NM_017433.5:c.4073G>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_017433.5(MYO3A):​c.4073G>C​(p.Arg1358Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,884 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1358Q) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: MYO3A NM_017433.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.96
• 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), 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYO3A	NM_017433.5	MANE Select	c.4073G>C	p.Arg1358Pro	missense	Exon 30 of 35	NP_059129.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYO3A	ENST00000642920.2	MANE Select	c.4073G>C	p.Arg1358Pro	missense	Exon 30 of 35	ENSP00000495965.1
	MYO3A	ENST00000543632.5	TSL:1	c.1777-37506G>C		intron	N/A	ENSP00000445909.1
	MYO3A	ENST00000647478.1		n.*1393+3798G>C		intron	N/A	ENSP00000493932.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461884 Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0 AN XY: 727242

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112010

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.68
BayesDel_addAF	Uncertain	0.071	D
BayesDel_noAF	Benign	-0.14
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.17	T
Eigen	Benign	0.041
Eigen_PC	Benign	-0.011
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.74	T
M_CAP	Uncertain	0.17	D
MetaRNN	Uncertain	0.58	D
MetaSVM	Uncertain	-0.011	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		3.0
PrimateAI	Benign	0.25	T
PROVEAN	Uncertain	-2.8	D
REVEL	Uncertain	0.54
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.055	T
Polyphen		0.99	D
Vest4		0.59
MutPred		0.38		Gain of glycosylation at R1358 (P = 0.0075)
MVP		0.86
MPC		0.43
ClinPred		0.97	D
GERP RS		2.8
Varity_R		0.56
gMVP		0.40
Mutation Taster		=76/24	polymorphism

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: rs141903506; hg19: chr10-26463266;