rs114982270

Variant names:

• chr10-26128445-T-C
• rs114982270
• NM_017433.5:c.2169T>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_017433.5(MYO3A):​c.2169T>C​(p.Asn723Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000742 in 1,612,832 control chromosomes in the GnomAD database, including 10 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 0.0042 (4 hom., cov: 33)
  • Exomes 𝑓: 0.00038 (6 hom.)
• Consequence: MYO3A NM_017433.5 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 1.19
• Publications: 1 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP6: Variant 10-26128445-T-C is Benign according to our data. Variant chr10-26128445-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 45802.
• BP7: Synonymous conserved (PhyloP=1.18 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00423 (643/152166) while in subpopulation AFR AF = 0.015 (622/41538). AF 95% confidence interval is 0.014. There are 4 homozygotes in GnomAd4. There are 272 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 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.2169T>C	p.Asn723Asn	synonymous	Exon 20 of 35	NP_059129.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYO3A	ENST00000642920.2	MANE Select	c.2169T>C	p.Asn723Asn	synonymous	Exon 20 of 35	ENSP00000495965.1
	MYO3A	ENST00000543632.5	TSL:1	c.1776+31763T>C		intron	N/A	ENSP00000445909.1
	MYO3A	ENST00000642197.1		n.2373T>C		non_coding_transcript_exon	Exon 20 of 27

Frequencies

GnomAD3 genomes AF: 0.00420 AC: 639 AN: 152048 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.0149

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000851

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: 0.0000441

Gnomad OTH AF: 0.00192

GnomAD2 exomes AF: 0.000957 AC: 240 AN: 250886 AF XY: 0.000553

Gnomad AFR exome AF: 0.0137

Gnomad AMR exome AF: 0.000405

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000327

GnomAD4 exome AF: 0.000379 AC: 553 AN: 1460666 Hom.: 6 Cov.: 31 AF XY: 0.000310 AC XY: 225 AN XY: 726722

African (AFR) AF: 0.0143 AC: 478 AN: 33438

American (AMR) AF: 0.000581 AC: 26 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26108

East Asian (EAS) AF: 0.00 AC: 0 AN: 39588

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86230

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53346

Middle Eastern (MID) AF: 0.000522 AC: 3 AN: 5752

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111148

Other (OTH) AF: 0.000713 AC: 43 AN: 60338

GnomAD4 genome AF: 0.00423 AC: 643 AN: 152166 Hom.: 4 Cov.: 33 AF XY: 0.00366 AC XY: 272 AN XY: 74386

African (AFR) AF: 0.0150 AC: 622 AN: 41538

American (AMR) AF: 0.000850 AC: 13 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10570

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

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 67964

Other (OTH) AF: 0.00190 AC: 4 AN: 2108

Alfa AF: 0.00241 Hom.: 2

Bravo AF: 0.00410

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	5.5
DANN	Benign	0.67
PhyloP100		1.2
Mutation Taster		=94/6	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: rs114982270; hg19: chr10-26417374;