NM_017433.5:c.-17-79C>T

Variant names:

• chr10-25952015-C-T
• rs17450092
• NM_017433.5:c.-17-79C>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.-17-79C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0415 in 1,043,426 control chromosomes in the GnomAD database, including 1,115 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.045 (194 hom., cov: 32)
  • Exomes 𝑓: 0.041 (921 hom.)
• Consequence: MYO3A NM_017433.5 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.150
• Publications: 2 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), 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 10-25952015-C-T is Benign according to our data. Variant chr10-25952015-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 682722.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0585 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.-17-79C>T		intron	N/A	NP_059129.3
	MYO3A	NM_001368265.1		c.-17-79C>T		intron	N/A	NP_001355194.1	Q8NEV4-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYO3A	ENST00000642920.2	MANE Select	c.-17-79C>T		intron	N/A	ENSP00000495965.1	Q8NEV4-1
	MYO3A	ENST00000543632.5	TSL:1	c.-17-79C>T		intron	N/A	ENSP00000445909.1	F5H0U9
	MYO3A	ENST00000376302.5	TSL:1	c.-17-79C>T		intron	N/A	ENSP00000365479.1	Q8NEV4-2

Frequencies

GnomAD3 genomes AF: 0.0446 AC: 6780 AN: 152014 Hom.: 193 Cov.: 32

Gnomad AFR AF: 0.0455

Gnomad AMI AF: 0.0385

Gnomad AMR AF: 0.0377

Gnomad ASJ AF: 0.0577

Gnomad EAS AF: 0.00193

Gnomad SAS AF: 0.0286

Gnomad FIN AF: 0.0385

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.0502

Gnomad OTH AF: 0.0474

GnomAD4 exome AF: 0.0410 AC: 36517 AN: 891294 Hom.: 921 AF XY: 0.0410 AC XY: 18715 AN XY: 456752

African (AFR) AF: 0.0427 AC: 897 AN: 20984

American (AMR) AF: 0.0281 AC: 944 AN: 33564

Ashkenazi Jewish (ASJ) AF: 0.0574 AC: 1204 AN: 20974

East Asian (EAS) AF: 0.00122 AC: 42 AN: 34498

South Asian (SAS) AF: 0.0303 AC: 2040 AN: 67426

European-Finnish (FIN) AF: 0.0359 AC: 1748 AN: 48646

Middle Eastern (MID) AF: 0.0660 AC: 197 AN: 2984

European-Non Finnish (NFE) AF: 0.0447 AC: 27792 AN: 621796

Other (OTH) AF: 0.0409 AC: 1653 AN: 40422

GnomAD4 genome AF: 0.0445 AC: 6776 AN: 152132 Hom.: 194 Cov.: 32 AF XY: 0.0431 AC XY: 3207 AN XY: 74374

African (AFR) AF: 0.0453 AC: 1881 AN: 41524

American (AMR) AF: 0.0377 AC: 575 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.0577 AC: 200 AN: 3466

East Asian (EAS) AF: 0.00193 AC: 10 AN: 5176

South Asian (SAS) AF: 0.0286 AC: 138 AN: 4824

European-Finnish (FIN) AF: 0.0385 AC: 407 AN: 10584

Middle Eastern (MID) AF: 0.0680 AC: 20 AN: 294

European-Non Finnish (NFE) AF: 0.0502 AC: 3411 AN: 67984

Other (OTH) AF: 0.0469 AC: 99 AN: 2110

Alfa AF: 0.0475 Hom.: 23

Bravo AF: 0.0448

Asia WGS AF: 0.0180 AC: 61 AN: 3476

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.66
DANN	Benign	0.65
PhyloP100		-0.15
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs17450092; hg19: chr10-26240944;