rs72787346

Variant names:

• chr10-26088402-C-T
• rs72787346
• NM_017433.5:c.1559C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_017433.5(MYO3A):​c.1559C>T​(p.Ala520Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00343 in 1,612,384 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0021 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0036 (13 hom.)
• Consequence: MYO3A NM_017433.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: 7.90
• Publications: 12 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: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.043385416).
• BP6: Variant 10-26088402-C-T is Benign according to our data. Variant chr10-26088402-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 45799.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00207 (316/152306) while in subpopulation NFE AF = 0.0037 (252/68028). AF 95% confidence interval is 0.00333. There are 0 homozygotes in GnomAd4. There are 133 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 13 AR,SD,AD gene

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.1559C>T	p.Ala520Val	missense	Exon 15 of 35	NP_059129.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYO3A	ENST00000642920.2	MANE Select	c.1559C>T	p.Ala520Val	missense	Exon 15 of 35	ENSP00000495965.1
	MYO3A	ENST00000543632.5	TSL:1	c.1559C>T	p.Ala520Val	missense	Exon 14 of 17	ENSP00000445909.1
	MYO3A	ENST00000916509.1		c.1559C>T	p.Ala520Val	missense	Exon 15 of 33	ENSP00000586568.1

Frequencies

GnomAD3 genomes AF: 0.00208 AC: 316 AN: 152188 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000748

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000916

Gnomad ASJ AF: 0.00230

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000565

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00370

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.00221 AC: 554 AN: 251114 AF XY: 0.00225

Gnomad AFR exome AF: 0.000801

Gnomad AMR exome AF: 0.00145

Gnomad ASJ exome AF: 0.00169

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000370

Gnomad NFE exome AF: 0.00392

Gnomad OTH exome AF: 0.00327

GnomAD4 exome AF: 0.00357 AC: 5213 AN: 1460078 Hom.: 13 Cov.: 31 AF XY: 0.00344 AC XY: 2496 AN XY: 726506

African (AFR) AF: 0.000419 AC: 14 AN: 33430

American (AMR) AF: 0.00136 AC: 61 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00134 AC: 35 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39622

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86228

European-Finnish (FIN) AF: 0.000562 AC: 30 AN: 53374

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5766

European-Non Finnish (NFE) AF: 0.00440 AC: 4882 AN: 1110484

Other (OTH) AF: 0.00305 AC: 184 AN: 60336

GnomAD4 genome AF: 0.00207 AC: 316 AN: 152306 Hom.: 0 Cov.: 32 AF XY: 0.00179 AC XY: 133 AN XY: 74476

African (AFR) AF: 0.000746 AC: 31 AN: 41564

American (AMR) AF: 0.000915 AC: 14 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00230 AC: 8 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.000565 AC: 6 AN: 10618

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00370 AC: 252 AN: 68028

Other (OTH) AF: 0.00142 AC: 3 AN: 2114

Alfa AF: 0.00345 Hom.: 4

Bravo AF: 0.00206

TwinsUK AF: 0.00297 AC: 11

ALSPAC AF: 0.00337 AC: 13

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.00419 AC: 36

ExAC AF: 0.00217 AC: 264

Asia WGS AF: 0.000867 AC: 4 AN: 3474

EpiCase AF: 0.00442

EpiControl AF: 0.00344

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (2)
-	1	-	Autosomal recessive nonsyndromic hearing loss 30 (1)
-	-	1	MYO3A-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.024	T
BayesDel_noAF	Pathogenic	0.19
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.60	D
Eigen	Pathogenic	0.96
Eigen_PC	Pathogenic	0.92
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.043	T
MetaSVM	Uncertain	0.77	D
MutationAssessor	Uncertain	2.3	M
PhyloP100		7.9
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-3.7	D
REVEL	Pathogenic	0.77
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0060	D
Polyphen		1.0	D
Vest4		0.80
MVP		0.93
MPC		0.25
ClinPred		0.025	T
GERP RS		5.8
Varity_R		0.68
gMVP		0.48
Mutation Taster		=91/9	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs72787346; hg19: chr10-26377331;