rs112195128

Variant names:

• chr10-26125465-T-C
• rs112195128
• NM_017433.5:c.1971T>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.1971T>C​(p.Thr657Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000837 in 1,614,066 control chromosomes in the GnomAD database, including 13 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 0.0046 (8 hom., cov: 32)
  • Exomes 𝑓: 0.00045 (5 hom.)
• Consequence: MYO3A NM_017433.5 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: -0.344
• Publications: 0 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=-0.56).
• BP6: Variant 10-26125465-T-C is Benign according to our data. Variant chr10-26125465-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 164617.
• BP7: Synonymous conserved (PhyloP=-0.344 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00458 (698/152310) while in subpopulation AFR AF = 0.0155 (643/41564). AF 95% confidence interval is 0.0145. There are 8 homozygotes in GnomAd4. There are 315 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 8 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.1971T>C	p.Thr657Thr	synonymous	Exon 19 of 35	NP_059129.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYO3A	ENST00000642920.2	MANE Select	c.1971T>C	p.Thr657Thr	synonymous	Exon 19 of 35	ENSP00000495965.1
	MYO3A	ENST00000543632.5	TSL:1	c.1776+28783T>C		intron	N/A	ENSP00000445909.1
	MYO3A	ENST00000916509.1		c.1971T>C	p.Thr657Thr	synonymous	Exon 19 of 33	ENSP00000586568.1

Frequencies

GnomAD3 genomes AF: 0.00456 AC: 694 AN: 152192 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.0154

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00314

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: 0.0000147

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00107 AC: 270 AN: 251186 AF XY: 0.000759

Gnomad AFR exome AF: 0.0144

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: 0.000447 AC: 653 AN: 1461756 Hom.: 5 Cov.: 31 AF XY: 0.000395 AC XY: 287 AN XY: 727174

African (AFR) AF: 0.0156 AC: 521 AN: 33478

American (AMR) AF: 0.00107 AC: 48 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39674

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.000694 AC: 4 AN: 5766

European-Non Finnish (NFE) AF: 0.00000989 AC: 11 AN: 1111918

Other (OTH) AF: 0.00108 AC: 65 AN: 60392

GnomAD4 genome AF: 0.00458 AC: 698 AN: 152310 Hom.: 8 Cov.: 32 AF XY: 0.00423 AC XY: 315 AN XY: 74470

African (AFR) AF: 0.0155 AC: 643 AN: 41564

American (AMR) AF: 0.00314 AC: 48 AN: 15288

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68038

Other (OTH) AF: 0.00284 AC: 6 AN: 2114

Alfa AF: 0.00263 Hom.: 1

Bravo AF: 0.00534

Asia WGS AF: 0.000866 AC: 3 AN: 3478

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	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_noAF	Benign	-0.56
CADD	Benign	3.5
DANN	Benign	0.61
PhyloP100		-0.34
Mutation Taster		=98/2	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: rs112195128; hg19: chr10-26414394;