rs35379457

Variant names:

• chr10-26068818-C-T
• rs35379457
• NM_017433.5:c.1104C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_017433.5(MYO3A):​c.1104C>T​(p.Tyr368Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.52 in 1,585,094 control chromosomes in the GnomAD database, including 220,702 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.47 (17865 hom., cov: 33)
  • Exomes 𝑓: 0.53 (202837 hom.)
• Consequence: MYO3A NM_017433.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.123
• Publications: 14 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):

• nonsyndromic genetic hearing loss

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• autosomal recessive nonsyndromic hearing loss 30

  Inheritance: SD, AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, PanelApp Australia, Labcorp Genetics (formerly Invitae)
• 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.38).
• BP6: Variant 10-26068818-C-T is Benign according to our data. Variant chr10-26068818-C-T is described in ClinVar as Benign. ClinVar VariationId is 45796.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.123 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.55 is higher than 0.05.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYO3A	NM_017433.5	MANE Select	c.1104C>T	p.Tyr368Tyr	synonymous	Exon 12 of 35	NP_059129.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYO3A	ENST00000642920.2	MANE Select	c.1104C>T	p.Tyr368Tyr	synonymous	Exon 12 of 35	ENSP00000495965.1
	MYO3A	ENST00000543632.5	TSL:1	c.1104C>T	p.Tyr368Tyr	synonymous	Exon 11 of 17	ENSP00000445909.1
	MYO3A	ENST00000916509.1		c.1104C>T	p.Tyr368Tyr	synonymous	Exon 12 of 33	ENSP00000586568.1

Frequencies

GnomAD3 genomes AF: 0.475 AC: 71993 AN: 151654 Hom.: 17861 Cov.: 33

Gnomad AFR AF: 0.359

Gnomad AMI AF: 0.433

Gnomad AMR AF: 0.410

Gnomad ASJ AF: 0.533

Gnomad EAS AF: 0.271

Gnomad SAS AF: 0.493

Gnomad FIN AF: 0.578

Gnomad MID AF: 0.602

Gnomad NFE AF: 0.555

Gnomad OTH AF: 0.476

GnomAD2 exomes AF: 0.478 AC: 119851 AN: 250570 AF XY: 0.490

Gnomad AFR exome AF: 0.353

Gnomad AMR exome AF: 0.318

Gnomad ASJ exome AF: 0.528

Gnomad EAS exome AF: 0.271

Gnomad FIN exome AF: 0.579

Gnomad NFE exome AF: 0.553

Gnomad OTH exome AF: 0.504

GnomAD4 exome AF: 0.525 AC: 752551 AN: 1433324 Hom.: 202837 Cov.: 33 AF XY: 0.526 AC XY: 375451 AN XY: 714322

African (AFR) AF: 0.356 AC: 11759 AN: 33034

American (AMR) AF: 0.330 AC: 14704 AN: 44576

Ashkenazi Jewish (ASJ) AF: 0.520 AC: 13445 AN: 25842

East Asian (EAS) AF: 0.262 AC: 10334 AN: 39448

South Asian (SAS) AF: 0.482 AC: 41232 AN: 85620

European-Finnish (FIN) AF: 0.575 AC: 30508 AN: 53058

Middle Eastern (MID) AF: 0.555 AC: 3168 AN: 5704

European-Non Finnish (NFE) AF: 0.549 AC: 596928 AN: 1086626

Other (OTH) AF: 0.513 AC: 30473 AN: 59416

GnomAD4 genome AF: 0.474 AC: 72009 AN: 151770 Hom.: 17865 Cov.: 33 AF XY: 0.474 AC XY: 35133 AN XY: 74148

African (AFR) AF: 0.359 AC: 14888 AN: 41436

American (AMR) AF: 0.409 AC: 6235 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.533 AC: 1843 AN: 3456

East Asian (EAS) AF: 0.271 AC: 1402 AN: 5170

South Asian (SAS) AF: 0.492 AC: 2375 AN: 4828

European-Finnish (FIN) AF: 0.578 AC: 6084 AN: 10524

Middle Eastern (MID) AF: 0.586 AC: 171 AN: 292

European-Non Finnish (NFE) AF: 0.555 AC: 37613 AN: 67794

Other (OTH) AF: 0.476 AC: 1005 AN: 2110

Alfa AF: 0.521 Hom.: 11927

Bravo AF: 0.451

Asia WGS AF: 0.397 AC: 1380 AN: 3476

EpiCase AF: 0.556

EpiControl AF: 0.560

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	2	Autosomal recessive nonsyndromic hearing loss 30 (2)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.38
CADD	Benign	2.4
DANN	Benign	0.44
PhyloP100		-0.12
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs35379457; hg19: chr10-26357747; COSMIC: COSV56322248;