10-26067063-A-G

Variant names:

• chr10-26067063-A-G
• rs3824699
• NM_017433.5:c.1042A>G

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.1042A>G​(p.Ile348Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.686 in 1,603,116 control chromosomes in the GnomAD database, including 378,441 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I348L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.69 (35977 hom., cov: 32)
  • Exomes 𝑓: 0.69 (342464 hom.)
• Consequence: MYO3A NM_017433.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 2.06
• Publications: 38 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.3441309E-6).
• BP6: Variant 10-26067063-A-G is Benign according to our data. Variant chr10-26067063-A-G is described in ClinVar as Benign. ClinVar VariationId is 45792.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.692 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.1042A>G	p.Ile348Val	missense	Exon 11 of 35	NP_059129.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYO3A	ENST00000642920.2	MANE Select	c.1042A>G	p.Ile348Val	missense	Exon 11 of 35	ENSP00000495965.1	Q8NEV4-1
	MYO3A	ENST00000543632.5	TSL:1	c.1042A>G	p.Ile348Val	missense	Exon 10 of 17	ENSP00000445909.1	F5H0U9
	MYO3A	ENST00000916509.1		c.1042A>G	p.Ile348Val	missense	Exon 11 of 33	ENSP00000586568.1

Frequencies

GnomAD3 genomes AF: 0.686 AC: 104265 AN: 151950 Hom.: 35943 Cov.: 32

Gnomad AFR AF: 0.682

Gnomad AMI AF: 0.532

Gnomad AMR AF: 0.631

Gnomad ASJ AF: 0.670

Gnomad EAS AF: 0.623

Gnomad SAS AF: 0.655

Gnomad FIN AF: 0.774

Gnomad MID AF: 0.772

Gnomad NFE AF: 0.697

Gnomad OTH AF: 0.686

GnomAD2 exomes AF: 0.676 AC: 169513 AN: 250758 AF XY: 0.677

Gnomad AFR exome AF: 0.675

Gnomad AMR exome AF: 0.622

Gnomad ASJ exome AF: 0.670

Gnomad EAS exome AF: 0.619

Gnomad FIN exome AF: 0.772

Gnomad NFE exome AF: 0.696

Gnomad OTH exome AF: 0.678

GnomAD4 exome AF: 0.685 AC: 994667 AN: 1451048 Hom.: 342464 Cov.: 33 AF XY: 0.684 AC XY: 494153 AN XY: 722420

African (AFR) AF: 0.685 AC: 22777 AN: 33260

American (AMR) AF: 0.622 AC: 27765 AN: 44662

Ashkenazi Jewish (ASJ) AF: 0.666 AC: 17332 AN: 26014

East Asian (EAS) AF: 0.620 AC: 24532 AN: 39554

South Asian (SAS) AF: 0.632 AC: 54323 AN: 85916

European-Finnish (FIN) AF: 0.767 AC: 40837 AN: 53264

Middle Eastern (MID) AF: 0.691 AC: 3961 AN: 5736

European-Non Finnish (NFE) AF: 0.691 AC: 762270 AN: 1102600

Other (OTH) AF: 0.681 AC: 40870 AN: 60042

GnomAD4 genome AF: 0.686 AC: 104353 AN: 152068 Hom.: 35977 Cov.: 32 AF XY: 0.688 AC XY: 51179 AN XY: 74342

African (AFR) AF: 0.683 AC: 28320 AN: 41486

American (AMR) AF: 0.631 AC: 9642 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.670 AC: 2322 AN: 3464

East Asian (EAS) AF: 0.623 AC: 3218 AN: 5166

South Asian (SAS) AF: 0.656 AC: 3159 AN: 4818

European-Finnish (FIN) AF: 0.774 AC: 8190 AN: 10586

Middle Eastern (MID) AF: 0.762 AC: 224 AN: 294

European-Non Finnish (NFE) AF: 0.697 AC: 47351 AN: 67956

Other (OTH) AF: 0.685 AC: 1443 AN: 2108

Alfa AF: 0.687 Hom.: 136949

Bravo AF: 0.673

ESP6500AA AF: 0.680 AC: 2996

ESP6500EA AF: 0.684 AC: 5881

ExAC AF: 0.678 AC: 82338

Asia WGS AF: 0.656 AC: 2281 AN: 3478

EpiCase AF: 0.692

EpiControl AF: 0.697

ClinVar

ClinVar submissions

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	-0.60	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	7.8
DANN	Benign	0.34
DEOGEN2	Benign	0.13	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.75
FATHMM_MKL	Benign	0.016	N
LIST_S2	Benign	0.27	T
MetaRNN	Benign	0.0000013	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	-0.83	N
PhyloP100		2.1
PrimateAI	Benign	0.35	T
PROVEAN	Benign	0.52	N
REVEL	Benign	0.11
Sift	Benign	1.0	T
Sift4G	Benign	0.78	T
Polyphen		0.0	B
Vest4		0.065
MPC		0.053
ClinPred		0.00051	T
GERP RS		2.7
Varity_R		0.029
gMVP		0.29
Mutation Taster		=100/0	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: rs3824699; hg19: chr10-26355992; COSMIC: COSV56319868;