NM_017433.5:c.3937C>A

Variant names:

• chr10-26174201-C-A
• rs1999240
• NM_017433.5:c.3937C>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.3937C>A​(p.Arg1313Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.587 in 1,613,926 control chromosomes in the GnomAD database, including 279,409 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 (★★).

• Frequency:
  • Genomes: 𝑓 0.58 (26113 hom., cov: 32)
  • Exomes 𝑓: 0.59 (253296 hom.)
• Consequence: MYO3A NM_017433.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 1.64
• Publications: 40 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=3.7209604E-6).
• BP6: Variant 10-26174201-C-A is Benign according to our data. Variant chr10-26174201-C-A is described in ClinVar as Benign. ClinVar VariationId is 45811.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.623 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.3937C>A	p.Arg1313Ser	missense	Exon 30 of 35	NP_059129.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYO3A	ENST00000642920.2	MANE Select	c.3937C>A	p.Arg1313Ser	missense	Exon 30 of 35	ENSP00000495965.1
	MYO3A	ENST00000543632.5	TSL:1	c.1777-37642C>A		intron	N/A	ENSP00000445909.1
	MYO3A	ENST00000916509.1		c.3937C>A	p.Arg1313Ser	missense	Exon 30 of 33	ENSP00000586568.1

Frequencies

GnomAD3 genomes AF: 0.584 AC: 88781 AN: 151940 Hom.: 26095 Cov.: 32

Gnomad AFR AF: 0.551

Gnomad AMI AF: 0.380

Gnomad AMR AF: 0.608

Gnomad ASJ AF: 0.585

Gnomad EAS AF: 0.642

Gnomad SAS AF: 0.621

Gnomad FIN AF: 0.655

Gnomad MID AF: 0.677

Gnomad NFE AF: 0.583

Gnomad OTH AF: 0.598

GnomAD2 exomes AF: 0.601 AC: 151112 AN: 251360 AF XY: 0.600

Gnomad AFR exome AF: 0.544

Gnomad AMR exome AF: 0.649

Gnomad ASJ exome AF: 0.589

Gnomad EAS exome AF: 0.628

Gnomad FIN exome AF: 0.659

Gnomad NFE exome AF: 0.581

Gnomad OTH exome AF: 0.603

GnomAD4 exome AF: 0.588 AC: 858963 AN: 1461868 Hom.: 253296 Cov.: 70 AF XY: 0.587 AC XY: 427232 AN XY: 727238

African (AFR) AF: 0.552 AC: 18489 AN: 33474

American (AMR) AF: 0.644 AC: 28800 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.585 AC: 15291 AN: 26136

East Asian (EAS) AF: 0.671 AC: 26647 AN: 39700

South Asian (SAS) AF: 0.600 AC: 51707 AN: 86250

European-Finnish (FIN) AF: 0.654 AC: 34929 AN: 53416

Middle Eastern (MID) AF: 0.615 AC: 3549 AN: 5768

European-Non Finnish (NFE) AF: 0.579 AC: 644289 AN: 1112006

Other (OTH) AF: 0.584 AC: 35262 AN: 60396

GnomAD4 genome AF: 0.584 AC: 88857 AN: 152058 Hom.: 26113 Cov.: 32 AF XY: 0.590 AC XY: 43816 AN XY: 74294

African (AFR) AF: 0.551 AC: 22840 AN: 41452

American (AMR) AF: 0.608 AC: 9286 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.585 AC: 2029 AN: 3470

East Asian (EAS) AF: 0.641 AC: 3317 AN: 5172

South Asian (SAS) AF: 0.621 AC: 2999 AN: 4826

European-Finnish (FIN) AF: 0.655 AC: 6924 AN: 10566

Middle Eastern (MID) AF: 0.663 AC: 195 AN: 294

European-Non Finnish (NFE) AF: 0.583 AC: 39656 AN: 67978

Other (OTH) AF: 0.598 AC: 1265 AN: 2114

Alfa AF: 0.582 Hom.: 132582

Bravo AF: 0.576

TwinsUK AF: 0.571 AC: 2118

ALSPAC AF: 0.587 AC: 2262

ESP6500AA AF: 0.545 AC: 2403

ESP6500EA AF: 0.572 AC: 4916

ExAC AF: 0.598 AC: 72658

Asia WGS AF: 0.625 AC: 2170 AN: 3478

EpiCase AF: 0.585

EpiControl AF: 0.586

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	11
DANN	Benign	0.27
DEOGEN2	Benign	0.037	T
Eigen	Benign	-0.87
Eigen_PC	Benign	-0.71
FATHMM_MKL	Benign	0.0083	N
LIST_S2	Benign	0.12	T
MetaRNN	Benign	0.0000037	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.0	N
PhyloP100		1.6
PrimateAI	Benign	0.30	T
PROVEAN	Benign	0.64	N
REVEL	Benign	0.23
Sift	Benign	1.0	T
Sift4G	Benign	0.74	T
Polyphen		0.0	B
Vest4		0.010
MPC		0.067
ClinPred		0.0018	T
GERP RS		4.1
Varity_R		0.083
gMVP		0.046
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: rs1999240; hg19: chr10-26463130; COSMIC: COSV56323764;