rs143918373

Variant names:

• chr10-26096461-C-A
• rs143918373
• NM_017433.5:c.1643C>A

Your query was ambiguous. Multiple possible variants found:

• chr10-26096461-C-A
• chr10-26096461-C-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.1643C>A​(p.Pro548His) variant causes a missense change. The variant allele was found at a frequency of 0.000315 in 1,613,648 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P548L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0012 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00022 (1 hom.)
• Consequence: MYO3A NM_017433.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:2
• Conservation: PhyloP100: 4.64
• 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), 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.012907296).
• BP6: Variant 10-26096461-C-A is Benign according to our data. Variant chr10-26096461-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 178465.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00122 (185/152226) while in subpopulation AFR AF = 0.00363 (151/41556). AF 95% confidence interval is 0.00316. There are 2 homozygotes in GnomAd4. There are 83 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 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.1643C>A	p.Pro548His	missense	Exon 16 of 35	NP_059129.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYO3A	ENST00000642920.2	MANE Select	c.1643C>A	p.Pro548His	missense	Exon 16 of 35	ENSP00000495965.1
	MYO3A	ENST00000543632.5	TSL:1	c.1643C>A	p.Pro548His	missense	Exon 15 of 17	ENSP00000445909.1
	MYO3A	ENST00000916509.1		c.1643C>A	p.Pro548His	missense	Exon 16 of 33	ENSP00000586568.1

Frequencies

GnomAD3 genomes AF: 0.00120 AC: 183 AN: 152108 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00360

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00151

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: 0.000103

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.000419 AC: 105 AN: 250834 AF XY: 0.000265

Gnomad AFR exome AF: 0.00346

Gnomad AMR exome AF: 0.000868

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000141

Gnomad OTH exome AF: 0.000656

GnomAD4 exome AF: 0.000222 AC: 324 AN: 1461422 Hom.: 1 Cov.: 31 AF XY: 0.000212 AC XY: 154 AN XY: 727018

African (AFR) AF: 0.00305 AC: 102 AN: 33472

American (AMR) AF: 0.000850 AC: 38 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.000191 AC: 5 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39638

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86200

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.000696 AC: 4 AN: 5750

European-Non Finnish (NFE) AF: 0.000124 AC: 138 AN: 1111726

Other (OTH) AF: 0.000596 AC: 36 AN: 60374

GnomAD4 genome AF: 0.00122 AC: 185 AN: 152226 Hom.: 2 Cov.: 32 AF XY: 0.00111 AC XY: 83 AN XY: 74448

African (AFR) AF: 0.00363 AC: 151 AN: 41556

American (AMR) AF: 0.00150 AC: 23 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

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: 0.000103 AC: 7 AN: 67998

Other (OTH) AF: 0.00189 AC: 4 AN: 2112

Alfa AF: 0.000449 Hom.: 0

Bravo AF: 0.00117

ESP6500AA AF: 0.00386 AC: 17

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000486 AC: 59

Asia WGS AF: 0.000578 AC: 2 AN: 3476

EpiCase AF: 0.000218

EpiControl AF: 0.000119

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	4	1	not provided (5)
-	1	-	Autosomal recessive nonsyndromic hearing loss 30 (1)
-	1	-	Inborn genetic diseases (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.29
CADD	Uncertain	24
DANN	Benign	0.96
DEOGEN2	Uncertain	0.50	D
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.048	D
MetaRNN	Benign	0.013	T
MetaSVM	Uncertain	0.16	D
MutationAssessor	Benign	1.6	L
PhyloP100		4.6
PrimateAI	Benign	0.46	T
PROVEAN	Uncertain	-3.4	D
REVEL	Uncertain	0.41
Sift	Benign	0.060	T
Sift4G	Benign	0.17	T
Polyphen		0.29	B
Vest4		0.49
MVP		0.83
MPC		0.076
ClinPred		0.035	T
GERP RS		3.3
Varity_R		0.35
gMVP		0.36
Mutation Taster		=89/11	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs143918373; hg19: chr10-26385390;