rs3817420

Variant names:

• chr10-26068819-G-A
• rs3817420
• NM_017433.5:c.1105G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_017433.5(MYO3A):​c.1105G>A​(p.Val369Ile) variant causes a missense change. The variant allele was found at a frequency of 0.686 in 1,586,116 control chromosomes in the GnomAD database, including 375,414 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.69 (36541 hom., cov: 33)
  • Exomes 𝑓: 0.68 (338873 hom.)
• Consequence: MYO3A NM_017433.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 4.23
• Publications: 31 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.2514962E-5).
• BP6: Variant 10-26068819-G-A is Benign according to our data. Variant chr10-26068819-G-A is described in ClinVar as Benign. ClinVar VariationId is 45797.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.698 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYO3A	NM_017433.5	MANE Select	c.1105G>A	p.Val369Ile	missense	Exon 12 of 35	NP_059129.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYO3A	ENST00000642920.2	MANE Select	c.1105G>A	p.Val369Ile	missense	Exon 12 of 35	ENSP00000495965.1
	MYO3A	ENST00000543632.5	TSL:1	c.1105G>A	p.Val369Ile	missense	Exon 11 of 17	ENSP00000445909.1
	MYO3A	ENST00000642197.1		n.1309G>A		non_coding_transcript_exon	Exon 12 of 27

Frequencies

GnomAD3 genomes AF: 0.692 AC: 105006 AN: 151690 Hom.: 36509 Cov.: 33

Gnomad AFR AF: 0.704

Gnomad AMI AF: 0.532

Gnomad AMR AF: 0.634

Gnomad ASJ AF: 0.669

Gnomad EAS AF: 0.622

Gnomad SAS AF: 0.654

Gnomad FIN AF: 0.773

Gnomad MID AF: 0.771

Gnomad NFE AF: 0.697

Gnomad OTH AF: 0.690

GnomAD2 exomes AF: 0.677 AC: 169753 AN: 250642 AF XY: 0.678

Gnomad AFR exome AF: 0.698

Gnomad AMR exome AF: 0.622

Gnomad ASJ exome AF: 0.670

Gnomad EAS exome AF: 0.618

Gnomad FIN exome AF: 0.771

Gnomad NFE exome AF: 0.696

Gnomad OTH exome AF: 0.679

GnomAD4 exome AF: 0.685 AC: 982490 AN: 1434310 Hom.: 338873 Cov.: 35 AF XY: 0.684 AC XY: 488683 AN XY: 714842

African (AFR) AF: 0.706 AC: 23350 AN: 33052

American (AMR) AF: 0.622 AC: 27743 AN: 44584

Ashkenazi Jewish (ASJ) AF: 0.666 AC: 17209 AN: 25850

East Asian (EAS) AF: 0.620 AC: 24462 AN: 39470

South Asian (SAS) AF: 0.632 AC: 54114 AN: 85658

European-Finnish (FIN) AF: 0.767 AC: 40702 AN: 53100

Middle Eastern (MID) AF: 0.691 AC: 3937 AN: 5700

European-Non Finnish (NFE) AF: 0.690 AC: 750484 AN: 1087438

Other (OTH) AF: 0.681 AC: 40489 AN: 59458

GnomAD4 genome AF: 0.692 AC: 105090 AN: 151806 Hom.: 36541 Cov.: 33 AF XY: 0.694 AC XY: 51496 AN XY: 74160

African (AFR) AF: 0.705 AC: 29193 AN: 41432

American (AMR) AF: 0.634 AC: 9667 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.669 AC: 2313 AN: 3458

East Asian (EAS) AF: 0.622 AC: 3216 AN: 5170

South Asian (SAS) AF: 0.654 AC: 3156 AN: 4822

European-Finnish (FIN) AF: 0.773 AC: 8145 AN: 10542

Middle Eastern (MID) AF: 0.760 AC: 222 AN: 292

European-Non Finnish (NFE) AF: 0.697 AC: 47242 AN: 67816

Other (OTH) AF: 0.689 AC: 1452 AN: 2108

Alfa AF: 0.690 Hom.: 91423

Bravo AF: 0.681

ESP6500AA AF: 0.682 AC: 3004

ESP6500EA AF: 0.659 AC: 5668

ExAC AF: 0.679 AC: 82486

Asia WGS AF: 0.654 AC: 2272 AN: 3476

EpiCase AF: 0.692

EpiControl AF: 0.696

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	2	Autosomal recessive nonsyndromic hearing loss 30 (2)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.059
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	14
DANN	Uncertain	0.98
DEOGEN2	Benign	0.25	T
Eigen	Benign	-0.64
Eigen_PC	Benign	-0.45
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.45	T
MetaRNN	Benign	0.000013	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	0.26	N
PhyloP100		4.2
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.66	N
REVEL	Benign	0.21
Sift	Benign	0.30	T
Sift4G	Benign	0.12	T
Polyphen		0.0010	B
Vest4		0.13
MPC		0.052
ClinPred		0.013	T
GERP RS		3.2
Varity_R		0.053
gMVP		0.54
Mutation Taster		=98/2	polymorphism (auto)

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: rs3817420; hg19: chr10-26357748; COSMIC: COSV56318367;