NM_017433.5:c.-18G>A

Variant names:

• chr10-25935830-G-A
• rs10128298
• NM_017433.5:c.-18G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 2P and 16B. PP3_Moderate BP6_Very_Strong BA1

The NM_017433.5(MYO3A):​c.-18G>A variant causes a splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0823 in 152,198 control chromosomes in the GnomAD database, including 667 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.082 (667 hom., cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: MYO3A NM_017433.5 splice_region
• Scores: Splicing: ADA: 0.9997
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.91
• Publications: 4 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 -14 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• BP6: Variant 10-25935830-G-A is Benign according to our data. Variant chr10-25935830-G-A is described in ClinVar as Benign. ClinVar VariationId is 299643.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.141 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.-18G>A		splice_region	Exon 2 of 35	NP_059129.3
	MYO3A	NM_017433.5	MANE Select	c.-18G>A		5_prime_UTR	Exon 2 of 35	NP_059129.3
	MYO3A	NM_001368265.1		c.-18G>A		splice_region	Exon 2 of 8	NP_001355194.1	Q8NEV4-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYO3A	ENST00000642920.2	MANE Select	c.-18G>A		splice_region	Exon 2 of 35	ENSP00000495965.1	Q8NEV4-1
	MYO3A	ENST00000543632.5	TSL:1	c.-18G>A		splice_region	Exon 1 of 17	ENSP00000445909.1	F5H0U9
	MYO3A	ENST00000376302.5	TSL:1	c.-18G>A		splice_region	Exon 2 of 8	ENSP00000365479.1	Q8NEV4-2

Frequencies

GnomAD3 genomes AF: 0.0822 AC: 12499 AN: 152080 Hom.: 666 Cov.: 32

Gnomad AFR AF: 0.144

Gnomad AMI AF: 0.148

Gnomad AMR AF: 0.0499

Gnomad ASJ AF: 0.0222

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00642

Gnomad FIN AF: 0.0905

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0654

Gnomad OTH AF: 0.0661

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 2 Hom.: 0 Cov.: 0 AC XY: 0 AN XY: 0

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 2

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AC: 0 AN: 0

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.0823 AC: 12521 AN: 152198 Hom.: 667 Cov.: 32 AF XY: 0.0818 AC XY: 6086 AN XY: 74412

African (AFR) AF: 0.144 AC: 5966 AN: 41510

American (AMR) AF: 0.0498 AC: 762 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0222 AC: 77 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5188

South Asian (SAS) AF: 0.00643 AC: 31 AN: 4822

European-Finnish (FIN) AF: 0.0905 AC: 958 AN: 10582

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0654 AC: 4450 AN: 68018

Other (OTH) AF: 0.0654 AC: 138 AN: 2110

Alfa AF: 0.0631 Hom.: 805

Bravo AF: 0.0821

Asia WGS AF: 0.00924 AC: 33 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	17
DANN	Benign	0.72
PhyloP100		1.9
PromoterAI		-0.033	Neutral
Mutation Taster		=280/20	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.90
SpliceAI score (max)		0.82		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.82		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs10128298; hg19: chr10-26224759;