rs3817419

Variant names:

• chr10-26068891-C-T
• rs3817419
• NM_017433.5:c.1170+7C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_017433.5(MYO3A):​c.1170+7C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.519 in 1,519,798 control chromosomes in the GnomAD database, including 209,500 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.48 (17950 hom., cov: 32)
  • Exomes 𝑓: 0.52 (191550 hom.)
• Consequence: MYO3A NM_017433.5 splice_region, intron
• Scores: Splicing: ADA: 0.00002746
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.829
• Publications: 13 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 10-26068891-C-T is Benign according to our data. Variant chr10-26068891-C-T is described in ClinVar as Benign. ClinVar VariationId is 45798.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.551 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.1170+7C>T		splice_region intron	N/A	NP_059129.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYO3A	ENST00000642920.2	MANE Select	c.1170+7C>T		splice_region intron	N/A	ENSP00000495965.1	Q8NEV4-1
	MYO3A	ENST00000543632.5	TSL:1	c.1170+7C>T		splice_region intron	N/A	ENSP00000445909.1	F5H0U9
	MYO3A	ENST00000916509.1		c.1170+7C>T		splice_region intron	N/A	ENSP00000586568.1

Frequencies

GnomAD3 genomes AF: 0.476 AC: 72155 AN: 151724 Hom.: 17945 Cov.: 32

Gnomad AFR AF: 0.360

Gnomad AMI AF: 0.433

Gnomad AMR AF: 0.410

Gnomad ASJ AF: 0.534

Gnomad EAS AF: 0.271

Gnomad SAS AF: 0.494

Gnomad FIN AF: 0.580

Gnomad MID AF: 0.604

Gnomad NFE AF: 0.555

Gnomad OTH AF: 0.477

GnomAD2 exomes AF: 0.478 AC: 119792 AN: 250382 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: 0.524 AC: 716395 AN: 1367956 Hom.: 191550 Cov.: 23 AF XY: 0.524 AC XY: 359402 AN XY: 685498

African (AFR) AF: 0.357 AC: 11211 AN: 31418

American (AMR) AF: 0.330 AC: 14657 AN: 44456

Ashkenazi Jewish (ASJ) AF: 0.520 AC: 13210 AN: 25414

East Asian (EAS) AF: 0.262 AC: 10235 AN: 39050

South Asian (SAS) AF: 0.482 AC: 40535 AN: 84120

European-Finnish (FIN) AF: 0.575 AC: 30345 AN: 52742

Middle Eastern (MID) AF: 0.558 AC: 3105 AN: 5562

European-Non Finnish (NFE) AF: 0.548 AC: 563707 AN: 1027920

Other (OTH) AF: 0.513 AC: 29390 AN: 57274

GnomAD4 genome AF: 0.475 AC: 72173 AN: 151842 Hom.: 17950 Cov.: 32 AF XY: 0.475 AC XY: 35234 AN XY: 74216

African (AFR) AF: 0.360 AC: 14911 AN: 41390

American (AMR) AF: 0.409 AC: 6248 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.534 AC: 1853 AN: 3468

East Asian (EAS) AF: 0.271 AC: 1404 AN: 5174

South Asian (SAS) AF: 0.493 AC: 2374 AN: 4814

European-Finnish (FIN) AF: 0.580 AC: 6117 AN: 10554

Middle Eastern (MID) AF: 0.588 AC: 173 AN: 294

European-Non Finnish (NFE) AF: 0.555 AC: 37692 AN: 67866

Other (OTH) AF: 0.478 AC: 1006 AN: 2106

Alfa AF: 0.524 Hom.: 7476

Bravo AF: 0.451

Asia WGS AF: 0.397 AC: 1382 AN: 3478

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)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	0.88
DANN	Benign	0.29
PhyloP100		-0.83
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000027
dbscSNV1_RF	Benign	0.0
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: rs3817419; hg19: chr10-26357820;