rs780657075

Positions:

• chr10-26024033-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_017433.5(MYO3A):​c.743C>G​(p.Pro248Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000089 in 1,460,686 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000089 (0 hom.)
• Consequence: MYO3A NM_017433.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 7.06

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.816

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYO3A	NM_017433.5	c.743C>G	p.Pro248Arg	missense_variant	9/35	ENST00000642920.2	NP_059129.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYO3A	ENST00000642920.2	c.743C>G	p.Pro248Arg	missense_variant	9/35		NM_017433.5	ENSP00000495965	P1
MYO3A	ENST00000543632.5	c.743C>G	p.Pro248Arg	missense_variant	8/17	1		ENSP00000445909
MYO3A	ENST00000642197.1	n.947C>G		non_coding_transcript_exon_variant	9/27
MYO3A	ENST00000647478.1	c.743C>G	p.Pro248Arg	missense_variant, NMD_transcript_variant	8/30			ENSP00000493932

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000398 AC: 10 AN: 251304 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135814

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000890 AC: 13 AN: 1460686 Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5 AN XY: 726708

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000246

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000151

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Aug 11, 2015

The p.Pro248Arg variant in MYO3A has not been previously reported in individuals with hearing loss, but has been identified in 1/11574 of Latino chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org). Althoug h this variant has been seen in the general population, its frequency is not hig h enough to rule out a pathogenic role. Computational prediction tools and conse rvation analyses suggest that the Pro248Arg variant may impact the protein, thou gh this information is not predictive enough to determine pathogenicity. In summ ary, the clinical significance of the Pro248Arg variant is uncertain. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Aug 24, 2021

Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Benign	-0.012	T
BayesDel_noAF	Uncertain	0.040
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.23	T;T;T
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	.;D;D
M_CAP	Uncertain	0.095	D
MetaRNN	Pathogenic	0.82	D;D;D
MetaSVM	Benign	-0.29	T
MutationAssessor	Uncertain	2.4	M;M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-8.0	.;D;D
REVEL	Uncertain	0.51
Sift	Uncertain	0.0010	.;D;D
Sift4G	Uncertain	0.0020	.;D;D
Polyphen		1.0	D;D;D
Vest4		0.70, 0.82
MutPred		0.65		Loss of glycosylation at P248 (P = 0.0046);Loss of glycosylation at P248 (P = 0.0046);Loss of glycosylation at P248 (P = 0.0046);
MVP		0.75
MPC		0.39
ClinPred		0.78	D
GERP RS		5.9
Varity_R		0.92
gMVP		0.81

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

Publications

LitVar

Other links and lift over

dbSNP: rs780657075; hg19: chr10-26312962;