10-26174514-C-T

Variant names:

• chr10-26174514-C-T
• rs34151474
• NM_017433.5:c.4250C>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.4250C>T​(p.Thr1417Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.012 in 1,613,830 control chromosomes in the GnomAD database, including 180 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0075 (9 hom., cov: 32)
  • Exomes 𝑓: 0.012 (171 hom.)
• Consequence: MYO3A NM_017433.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 0.133
• Publications: 9 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):

• nonsyndromic genetic hearing loss

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• autosomal recessive nonsyndromic hearing loss 30

  Inheritance: SD, AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, PanelApp Australia, Labcorp Genetics (formerly Invitae)
• 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=0.005092174).
• BP6: Variant 10-26174514-C-T is Benign according to our data. Variant chr10-26174514-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 45813.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00747 (1137/152236) while in subpopulation NFE AF = 0.013 (882/68016). AF 95% confidence interval is 0.0123. There are 9 homozygotes in GnomAd4. There are 490 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 9 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.4250C>T	p.Thr1417Ile	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.4250C>T	p.Thr1417Ile	missense	Exon 30 of 35	ENSP00000495965.1	Q8NEV4-1
	MYO3A	ENST00000543632.5	TSL:1	c.1777-37329C>T		intron	N/A	ENSP00000445909.1	F5H0U9
	MYO3A	ENST00000916509.1		c.4250C>T	p.Thr1417Ile	missense	Exon 30 of 33	ENSP00000586568.1

Frequencies

GnomAD3 genomes AF: 0.00748 AC: 1138 AN: 152118 Hom.: 9 Cov.: 32

Gnomad AFR AF: 0.00256

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00550

Gnomad ASJ AF: 0.00605

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00311

Gnomad FIN AF: 0.00160

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0130

Gnomad OTH AF: 0.00527

GnomAD2 exomes AF: 0.00748 AC: 1868 AN: 249594 AF XY: 0.00750

Gnomad AFR exome AF: 0.00198

Gnomad AMR exome AF: 0.00325

Gnomad ASJ exome AF: 0.00588

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00189

Gnomad NFE exome AF: 0.0135

Gnomad OTH exome AF: 0.00855

GnomAD4 exome AF: 0.0125 AC: 18266 AN: 1461594 Hom.: 171 Cov.: 35 AF XY: 0.0123 AC XY: 8932 AN XY: 727066

African (AFR) AF: 0.00200 AC: 67 AN: 33460

American (AMR) AF: 0.00340 AC: 152 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.00655 AC: 171 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00237 AC: 204 AN: 86162

European-Finnish (FIN) AF: 0.00311 AC: 166 AN: 53390

Middle Eastern (MID) AF: 0.00416 AC: 24 AN: 5766

European-Non Finnish (NFE) AF: 0.0152 AC: 16921 AN: 1111906

Other (OTH) AF: 0.00929 AC: 561 AN: 60392

GnomAD4 genome AF: 0.00747 AC: 1137 AN: 152236 Hom.: 9 Cov.: 32 AF XY: 0.00658 AC XY: 490 AN XY: 74458

African (AFR) AF: 0.00255 AC: 106 AN: 41528

American (AMR) AF: 0.00549 AC: 84 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00605 AC: 21 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00290 AC: 14 AN: 4820

European-Finnish (FIN) AF: 0.00160 AC: 17 AN: 10596

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0130 AC: 882 AN: 68016

Other (OTH) AF: 0.00521 AC: 11 AN: 2110

Alfa AF: 0.0115 Hom.: 26

Bravo AF: 0.00776

TwinsUK AF: 0.0151 AC: 56

ALSPAC AF: 0.0150 AC: 58

ESP6500AA AF: 0.00318 AC: 14

ESP6500EA AF: 0.0147 AC: 126

ExAC AF: 0.00772 AC: 937

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.0129

EpiControl AF: 0.0125

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	0.56
DANN	Benign	0.23
DEOGEN2	Benign	0.070	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.026	N
LIST_S2	Benign	0.47	T
MetaRNN	Benign	0.0051	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-0.60	N
PhyloP100		0.13
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-0.49	N
REVEL	Benign	0.17
Sift	Benign	0.41	T
Sift4G	Benign	0.21	T
Polyphen		0.0	B
Vest4		0.025
MVP		0.43
MPC		0.065
ClinPred		0.00078	T
GERP RS		0.97
Varity_R		0.064
gMVP		0.023
Mutation Taster		=95/5	polymorphism

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: rs34151474; hg19: chr10-26463443;