NM_017433.5:c.2168A>G

Variant names:

• chr10-26128444-A-G
• rs771154512
• NM_017433.5:c.2168A>G

Variant summary

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

The NM_017433.5(MYO3A):​c.2168A>G​(p.Asn723Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000992 in 1,612,808 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: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: MYO3A NM_017433.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 9.32

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, 0.819

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYO3A	NM_017433.5	c.2168A>G	p.Asn723Ser	missense_variant	Exon 20 of 35	ENST00000642920.2	NP_059129.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYO3A	ENST00000642920.2	c.2168A>G	p.Asn723Ser	missense_variant	Exon 20 of 35		NM_017433.5	ENSP00000495965.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152174 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000103 AC: 15 AN: 1460634 Hom.: 0 Cov.: 31 AF XY: 0.00000826 AC XY: 6 AN XY: 726720

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000117

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152174 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74324

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Aug 16, 2018

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Asn723Ser variant in MYO3A has not been previously reported in individuals with hearing loss. It has been identified in 1/66566 European chromosomes by th e Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs77 1154512); however, its frequency is not high enough to rule out a pathogenic rol e. Computational prediction tools and conservation analysis suggest that the p.A sn723Ser variant may impact the protein, though this information is not predicti ve enough to determine pathogenicity. In summary, the clinical significance of t he p.Asn723Ser variant is uncertain. ACMG/AMP Criteria applied: PP3, PM2. -

not provided Uncertain:1

Jan 05, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Uncertain	0.051	T
BayesDel_noAF	Benign	-0.16
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.42	T;T
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	.;D
M_CAP	Uncertain	0.088	D
MetaRNN	Pathogenic	0.82	D;D
MetaSVM	Uncertain	0.44	D
MutationAssessor	Benign	0.88	L;L
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-4.7	.;D
REVEL	Uncertain	0.62
Sift	Uncertain	0.0030	.;D
Sift4G	Uncertain	0.011	.;D
Polyphen		1.0	D;D
Vest4		0.88
MutPred		0.54		Loss of ubiquitination at K726 (P = 0.0982);Loss of ubiquitination at K726 (P = 0.0982);
MVP		0.94
MPC		0.33
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.68
gMVP		0.31

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: rs771154512; hg19: chr10-26417373;