rs4592324

Variant names:

• chr10-26120662-G-T
• rs4592324
• NM_017433.5:c.1777-14G>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.1777-14G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000701 in 1,613,830 control chromosomes in the GnomAD database, including 8 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 0.0039 (3 hom., cov: 31)
  • Exomes 𝑓: 0.00037 (5 hom.)
• Consequence: MYO3A NM_017433.5 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: -2.42
• 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), 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 (BayesDel_noAF=-0.91).
• BP6: Variant 10-26120662-G-T is Benign according to our data. Variant chr10-26120662-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 164618.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00387 (589/152240) while in subpopulation AFR AF = 0.0135 (562/41540). AF 95% confidence interval is 0.0126. There are 3 homozygotes in GnomAd4. There are 284 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYO3A	NM_017433.5	MANE Select	c.1777-14G>T		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.1777-14G>T		intron	N/A	ENSP00000495965.1	Q8NEV4-1
	MYO3A	ENST00000543632.5	TSL:1	c.1776+23980G>T		intron	N/A	ENSP00000445909.1	F5H0U9
	MYO3A	ENST00000916509.1		c.1777-14G>T		intron	N/A	ENSP00000586568.1

Frequencies

GnomAD3 genomes AF: 0.00385 AC: 586 AN: 152122 Hom.: 3 Cov.: 31

Gnomad AFR AF: 0.0135

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00105

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: 0.00383

GnomAD2 exomes AF: 0.00105 AC: 264 AN: 251088 AF XY: 0.000700

Gnomad AFR exome AF: 0.0140

Gnomad AMR exome AF: 0.000810

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.000653

GnomAD4 exome AF: 0.000371 AC: 542 AN: 1461590 Hom.: 5 Cov.: 31 AF XY: 0.000286 AC XY: 208 AN XY: 727110

African (AFR) AF: 0.0129 AC: 431 AN: 33472

American (AMR) AF: 0.000783 AC: 35 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39664

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53302

Middle Eastern (MID) AF: 0.000694 AC: 4 AN: 5762

European-Non Finnish (NFE) AF: 0.0000108 AC: 12 AN: 1111896

Other (OTH) AF: 0.000944 AC: 57 AN: 60388

GnomAD4 genome AF: 0.00387 AC: 589 AN: 152240 Hom.: 3 Cov.: 31 AF XY: 0.00382 AC XY: 284 AN XY: 74426

African (AFR) AF: 0.0135 AC: 562 AN: 41540

American (AMR) AF: 0.00105 AC: 16 AN: 15296

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68014

Other (OTH) AF: 0.00379 AC: 8 AN: 2112

Alfa AF: 0.00200 Hom.: 0

Bravo AF: 0.00435

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

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	-0.91
CADD	Benign	0.0020
DANN	Benign	0.49
PhyloP100		-2.4
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: rs4592324; hg19: chr10-26409591;