rs16926628

Variant names:

• chr10-26168708-T-C
• rs16926628
• NM_017433.5:c.3112-4T>C

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_017433.5(MYO3A):​c.3112-4T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.11 in 1,610,790 control chromosomes in the GnomAD database, including 10,752 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 0.12 (1317 hom., cov: 33)
  • Exomes 𝑓: 0.11 (9435 hom.)
• Consequence: MYO3A NM_017433.5 splice_region, intron
• Scores: Splicing: ADA: 0.0001928
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.378
• Publications: 7 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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 10-26168708-T-C is Benign according to our data. Variant chr10-26168708-T-C is described in ClinVar as Benign. ClinVar VariationId is 45807.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.169 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.3112-4T>C		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.3112-4T>C		splice_region intron	N/A	ENSP00000495965.1	Q8NEV4-1
	MYO3A	ENST00000543632.5	TSL:1	c.1777-43135T>C		intron	N/A	ENSP00000445909.1	F5H0U9
	MYO3A	ENST00000916509.1		c.3112-4T>C		splice_region intron	N/A	ENSP00000586568.1

Frequencies

GnomAD3 genomes AF: 0.124 AC: 18787 AN: 152100 Hom.: 1316 Cov.: 33

Gnomad AFR AF: 0.172

Gnomad AMI AF: 0.175

Gnomad AMR AF: 0.0876

Gnomad ASJ AF: 0.0778

Gnomad EAS AF: 0.00192

Gnomad SAS AF: 0.0345

Gnomad FIN AF: 0.128

Gnomad MID AF: 0.0823

Gnomad NFE AF: 0.119

Gnomad OTH AF: 0.106

GnomAD2 exomes AF: 0.0925 AC: 23169 AN: 250372 AF XY: 0.0912

Gnomad AFR exome AF: 0.175

Gnomad AMR exome AF: 0.0511

Gnomad ASJ exome AF: 0.0742

Gnomad EAS exome AF: 0.00234

Gnomad FIN exome AF: 0.123

Gnomad NFE exome AF: 0.119

Gnomad OTH exome AF: 0.0832

GnomAD4 exome AF: 0.108 AC: 157964 AN: 1458572 Hom.: 9435 Cov.: 31 AF XY: 0.106 AC XY: 77034 AN XY: 725760

African (AFR) AF: 0.172 AC: 5762 AN: 33414

American (AMR) AF: 0.0536 AC: 2394 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.0755 AC: 1972 AN: 26104

East Asian (EAS) AF: 0.00136 AC: 54 AN: 39598

South Asian (SAS) AF: 0.0370 AC: 3188 AN: 86164

European-Finnish (FIN) AF: 0.123 AC: 6469 AN: 52788

Middle Eastern (MID) AF: 0.0688 AC: 371 AN: 5396

European-Non Finnish (NFE) AF: 0.119 AC: 131620 AN: 1110142

Other (OTH) AF: 0.102 AC: 6134 AN: 60264

GnomAD4 genome AF: 0.124 AC: 18799 AN: 152218 Hom.: 1317 Cov.: 33 AF XY: 0.122 AC XY: 9044 AN XY: 74430

African (AFR) AF: 0.172 AC: 7144 AN: 41532

American (AMR) AF: 0.0874 AC: 1336 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0778 AC: 270 AN: 3470

East Asian (EAS) AF: 0.00193 AC: 10 AN: 5188

South Asian (SAS) AF: 0.0344 AC: 166 AN: 4832

European-Finnish (FIN) AF: 0.128 AC: 1359 AN: 10590

Middle Eastern (MID) AF: 0.0850 AC: 25 AN: 294

European-Non Finnish (NFE) AF: 0.119 AC: 8108 AN: 68000

Other (OTH) AF: 0.105 AC: 221 AN: 2110

Alfa AF: 0.114 Hom.: 2036

Bravo AF: 0.125

Asia WGS AF: 0.0270 AC: 93 AN: 3476

EpiCase AF: 0.110

EpiControl AF: 0.114

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	not provided (2)
-	-	1	Autosomal recessive nonsyndromic hearing loss 30 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Benign	11
DANN	Benign	0.72
PhyloP100		0.38
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00019
dbscSNV1_RF	Benign	0.010
SpliceAI score (max)		0.020		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: rs16926628; hg19: chr10-26457637;