ENST00000543632.5:c.1894C>G

Variant names:

• chr10-26211960-C-G
• rs56316209
• ENST00000543632.5:c.1894C>G

Variant summary

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

The ENST00000543632.5(MYO3A):​c.1894C>G​(p.Leu632Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00447 in 1,612,298 control chromosomes in the GnomAD database, including 251 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/17 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. L632P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.023 (143 hom., cov: 32)
  • Exomes 𝑓: 0.0025 (108 hom.)
• Consequence: MYO3A ENST00000543632.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.539
• 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), 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=0.0024323165).
• BP6: Variant 10-26211960-C-G is Benign according to our data. Variant chr10-26211960-C-G is described in ClinVar as Benign. ClinVar VariationId is 45818.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.074 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000543632.5. 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.4848C>G	p.Ser1616Ser	synonymous	Exon 35 of 35	NP_059129.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYO3A	ENST00000543632.5	TSL:1	c.1894C>G	p.Leu632Val	missense	Exon 17 of 17	ENSP00000445909.1	F5H0U9
	MYO3A	ENST00000642920.2	MANE Select	c.4848C>G	p.Ser1616Ser	synonymous	Exon 35 of 35	ENSP00000495965.1	Q8NEV4-1
	MYO3A	ENST00000916509.1		c.4596C>G	p.Ser1532Ser	synonymous	Exon 33 of 33	ENSP00000586568.1

Frequencies

GnomAD3 genomes AF: 0.0228 AC: 3465 AN: 152186 Hom.: 137 Cov.: 32

Gnomad AFR AF: 0.0755

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0180

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: 0.000426

Gnomad OTH AF: 0.0158

GnomAD2 exomes AF: 0.00615 AC: 1535 AN: 249400 AF XY: 0.00473

Gnomad AFR exome AF: 0.0781

Gnomad AMR exome AF: 0.00633

Gnomad ASJ exome AF: 0.000399

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000373

Gnomad OTH exome AF: 0.00329

GnomAD4 exome AF: 0.00254 AC: 3711 AN: 1459994 Hom.: 108 Cov.: 32 AF XY: 0.00223 AC XY: 1619 AN XY: 725924

African (AFR) AF: 0.0785 AC: 2626 AN: 33440

American (AMR) AF: 0.00741 AC: 331 AN: 44662

Ashkenazi Jewish (ASJ) AF: 0.000536 AC: 14 AN: 26100

East Asian (EAS) AF: 0.00 AC: 0 AN: 39632

South Asian (SAS) AF: 0.000162 AC: 14 AN: 86170

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53356

Middle Eastern (MID) AF: 0.00487 AC: 28 AN: 5754

European-Non Finnish (NFE) AF: 0.000318 AC: 353 AN: 1110606

Other (OTH) AF: 0.00572 AC: 345 AN: 60274

GnomAD4 genome AF: 0.0230 AC: 3504 AN: 152304 Hom.: 143 Cov.: 32 AF XY: 0.0231 AC XY: 1723 AN XY: 74482

African (AFR) AF: 0.0762 AC: 3167 AN: 41550

American (AMR) AF: 0.0180 AC: 275 AN: 15308

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

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

European-Non Finnish (NFE) AF: 0.000426 AC: 29 AN: 68030

Other (OTH) AF: 0.0156 AC: 33 AN: 2114

Alfa AF: 0.00699 Hom.: 11

Bravo AF: 0.0253

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.0722 AC: 318

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.00691 AC: 839

Asia WGS AF: 0.00808 AC: 28 AN: 3478

EpiCase AF: 0.000545

EpiControl AF: 0.000475

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Uncertain	-0.060
CADD	Benign	3.0
DANN	Benign	0.64
DEOGEN2	Benign	0.013	T
Eigen	Benign	-0.69
Eigen_PC	Benign	-0.63
FATHMM_MKL	Benign	0.23	N
LIST_S2	Benign	0.26	T
MetaRNN	Benign	0.0024	T
MetaSVM	Benign	-0.95	T
PhyloP100		0.54
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.26
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.34	T
Polyphen		0.0010	B
Vest4		0.088
MVP		0.62
ClinPred		0.11	T
GERP RS		1.5
Mutation Taster		=99/1	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: rs56316209; hg19: chr10-26500889;