10-26066977-G-T

Variant names:

• chr10-26066977-G-T
• rs3824700
• NM_017433.5:c.956G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_017433.5(MYO3A):​c.956G>T​(p.Arg319Leu) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000138 in 1,453,890 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. 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. R319H) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: MYO3A NM_017433.5 missense, splice_region
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.70
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.099447995).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYO3A	NM_017433.5	c.956G>T	p.Arg319Leu	missense_variant, splice_region_variant	Exon 11 of 35	ENST00000642920.2	NP_059129.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYO3A	ENST00000642920.2	c.956G>T	p.Arg319Leu	missense_variant, splice_region_variant	Exon 11 of 35		NM_017433.5	ENSP00000495965.1
MYO3A	ENST00000543632.5	c.956G>T	p.Arg319Leu	missense_variant, splice_region_variant	Exon 10 of 17	1		ENSP00000445909.1
MYO3A	ENST00000642197.1	n.1160G>T		splice_region_variant, non_coding_transcript_exon_variant	Exon 11 of 27
MYO3A	ENST00000647478.1	n.956G>T		splice_region_variant, non_coding_transcript_exon_variant	Exon 10 of 30			ENSP00000493932.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1453890 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 723736

African (AFR) AF: 0.00 AC: 0 AN: 33340

American (AMR) AF: 0.0000224 AC: 1 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26092

East Asian (EAS) AF: 0.00 AC: 0 AN: 39608

South Asian (SAS) AF: 0.00 AC: 0 AN: 86110

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53338

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5750

European-Non Finnish (NFE) AF: 9.05e-7 AC: 1 AN: 1104834

Other (OTH) AF: 0.00 AC: 0 AN: 60116

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.069	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.087	T;T;T
Eigen	Benign	-0.46
Eigen_PC	Benign	-0.23
FATHMM_MKL	Benign	0.66	D
LIST_S2	Benign	0.86	.;D;T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.099	T;T;T
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	0.0	N;N;.
PhyloP100		3.7
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-1.7	.;N;N
REVEL	Benign	0.24
Sift	Benign	0.067	.;T;T
Sift4G	Benign	0.13	.;T;T
Polyphen		0.0020	B;B;B
Vest4		0.23, 0.22
MutPred		0.38		Loss of MoRF binding (P = 0.0437);Loss of MoRF binding (P = 0.0437);Loss of MoRF binding (P = 0.0437);
MVP		0.80
MPC		0.074
ClinPred		0.84	D
GERP RS		5.6
Varity_R		0.12
gMVP		0.35
Mutation Taster		=97/3	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: rs3824700; hg19: chr10-26355906;