chr10-25954882-C-T

Variant names:

• chr10-25954882-C-T
• rs139958275
• NM_017433.5:c.177C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Moderate BP6 BP7 BS1 BS2

The NM_017433.5(MYO3A):​c.177C>T​(p.Asp59Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00111 in 1,611,846 control chromosomes in the GnomAD database, including 6 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 0.00090 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (6 hom.)
• Consequence: MYO3A NM_017433.5 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 1.48
• Publications: 3 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.34).
• BP6: Variant 10-25954882-C-T is Benign according to our data. Variant chr10-25954882-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 164603.
• BP7: Synonymous conserved (PhyloP=1.48 with no splicing effect.
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.00113 (1654/1459760) while in subpopulation MID AF = 0.0105 (60/5720). AF 95% confidence interval is 0.00837. There are 6 homozygotes in GnomAdExome4. There are 904 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 6 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.177C>T	p.Asp59Asp	synonymous	Exon 4 of 35	NP_059129.3
	MYO3A	NM_001368265.1		c.177C>T	p.Asp59Asp	synonymous	Exon 4 of 8	NP_001355194.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYO3A	ENST00000642920.2	MANE Select	c.177C>T	p.Asp59Asp	synonymous	Exon 4 of 35	ENSP00000495965.1
	MYO3A	ENST00000543632.5	TSL:1	c.177C>T	p.Asp59Asp	synonymous	Exon 3 of 17	ENSP00000445909.1
	MYO3A	ENST00000376302.5	TSL:1	c.177C>T	p.Asp59Asp	synonymous	Exon 4 of 8	ENSP00000365479.1

Frequencies

GnomAD3 genomes AF: 0.000895 AC: 136 AN: 151968 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.0190

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00187

Gnomad FIN AF: 0.0000945

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000574

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.00151 AC: 378 AN: 250690 AF XY: 0.00169

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.000667

Gnomad ASJ exome AF: 0.0163

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.000324

Gnomad NFE exome AF: 0.000848

Gnomad OTH exome AF: 0.00262

GnomAD4 exome AF: 0.00113 AC: 1654 AN: 1459760 Hom.: 6 Cov.: 31 AF XY: 0.00124 AC XY: 904 AN XY: 726268

African (AFR) AF: 0.000778 AC: 26 AN: 33406

American (AMR) AF: 0.000762 AC: 34 AN: 44616

Ashkenazi Jewish (ASJ) AF: 0.0164 AC: 428 AN: 26054

East Asian (EAS) AF: 0.0000758 AC: 3 AN: 39592

South Asian (SAS) AF: 0.00179 AC: 154 AN: 86194

European-Finnish (FIN) AF: 0.000431 AC: 23 AN: 53342

Middle Eastern (MID) AF: 0.0105 AC: 60 AN: 5720

European-Non Finnish (NFE) AF: 0.000726 AC: 806 AN: 1110564

Other (OTH) AF: 0.00199 AC: 120 AN: 60272

GnomAD4 genome AF: 0.000901 AC: 137 AN: 152086 Hom.: 0 Cov.: 32 AF XY: 0.000807 AC XY: 60 AN XY: 74326

African (AFR) AF: 0.000193 AC: 8 AN: 41498

American (AMR) AF: 0.000262 AC: 4 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.0190 AC: 66 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00187 AC: 9 AN: 4816

European-Finnish (FIN) AF: 0.0000945 AC: 1 AN: 10584

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000589 AC: 40 AN: 67956

Other (OTH) AF: 0.00331 AC: 7 AN: 2114

Alfa AF: 0.00161 Hom.: 0

Bravo AF: 0.000986

Asia WGS AF: 0.000578 AC: 2 AN: 3476

EpiCase AF: 0.00131

EpiControl AF: 0.00124

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.34
CADD	Benign	6.1
DANN	Benign	0.62
PhyloP100		1.5
Mutation Taster		=91/9	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: rs139958275; hg19: chr10-26243811; COSMIC: COSV56338879;