10-26145526-G-T

Variant names:

• chr10-26145526-G-T
• rs33947968
• NM_017433.5:c.2497G>T

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.2497G>T​(p.Ala833Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0765 in 1,591,708 control chromosomes in the GnomAD database, including 5,298 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A833P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.061 (368 hom., cov: 32)
  • Exomes 𝑓: 0.078 (4930 hom.)
• Consequence: MYO3A NM_017433.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 10.0
• Publications: 20 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=0.010160327).
• BP6: Variant 10-26145526-G-T is Benign according to our data. Variant chr10-26145526-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 45803.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0866 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.2497G>T	p.Ala833Ser	missense	Exon 22 of 35	NP_059129.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYO3A	ENST00000642920.2	MANE Select	c.2497G>T	p.Ala833Ser	missense	Exon 22 of 35	ENSP00000495965.1	Q8NEV4-1
	MYO3A	ENST00000543632.5	TSL:1	c.1776+48844G>T		intron	N/A	ENSP00000445909.1	F5H0U9
	MYO3A	ENST00000916509.1		c.2497G>T	p.Ala833Ser	missense	Exon 22 of 33	ENSP00000586568.1

Frequencies

GnomAD3 genomes AF: 0.0611 AC: 9295 AN: 152096 Hom.: 368 Cov.: 32

Gnomad AFR AF: 0.0178

Gnomad AMI AF: 0.0263

Gnomad AMR AF: 0.0744

Gnomad ASJ AF: 0.0975

Gnomad EAS AF: 0.000963

Gnomad SAS AF: 0.0276

Gnomad FIN AF: 0.0689

Gnomad MID AF: 0.0791

Gnomad NFE AF: 0.0885

Gnomad OTH AF: 0.0700

GnomAD2 exomes AF: 0.0637 AC: 15940 AN: 250250 AF XY: 0.0646

Gnomad AFR exome AF: 0.0178

Gnomad AMR exome AF: 0.0502

Gnomad ASJ exome AF: 0.0926

Gnomad EAS exome AF: 0.000600

Gnomad FIN exome AF: 0.0697

Gnomad NFE exome AF: 0.0894

Gnomad OTH exome AF: 0.0773

GnomAD4 exome AF: 0.0781 AC: 112399 AN: 1439494 Hom.: 4930 Cov.: 30 AF XY: 0.0770 AC XY: 55262 AN XY: 717456

African (AFR) AF: 0.0160 AC: 527 AN: 32988

American (AMR) AF: 0.0527 AC: 2356 AN: 44688

Ashkenazi Jewish (ASJ) AF: 0.0912 AC: 2370 AN: 26000

East Asian (EAS) AF: 0.000303 AC: 12 AN: 39556

South Asian (SAS) AF: 0.0308 AC: 2641 AN: 85784

European-Finnish (FIN) AF: 0.0725 AC: 3871 AN: 53370

Middle Eastern (MID) AF: 0.0451 AC: 258 AN: 5716

European-Non Finnish (NFE) AF: 0.0878 AC: 95893 AN: 1091686

Other (OTH) AF: 0.0749 AC: 4471 AN: 59706

GnomAD4 genome AF: 0.0610 AC: 9291 AN: 152214 Hom.: 368 Cov.: 32 AF XY: 0.0597 AC XY: 4444 AN XY: 74414

African (AFR) AF: 0.0177 AC: 737 AN: 41542

American (AMR) AF: 0.0744 AC: 1138 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0975 AC: 338 AN: 3466

East Asian (EAS) AF: 0.000965 AC: 5 AN: 5182

South Asian (SAS) AF: 0.0274 AC: 132 AN: 4814

European-Finnish (FIN) AF: 0.0689 AC: 730 AN: 10598

Middle Eastern (MID) AF: 0.0782 AC: 23 AN: 294

European-Non Finnish (NFE) AF: 0.0885 AC: 6016 AN: 68004

Other (OTH) AF: 0.0702 AC: 148 AN: 2108

Alfa AF: 0.0785 Hom.: 1979

Bravo AF: 0.0606

TwinsUK AF: 0.0863 AC: 320

ALSPAC AF: 0.0926 AC: 357

ESP6500AA AF: 0.0204 AC: 90

ESP6500EA AF: 0.0933 AC: 802

ExAC AF: 0.0638 AC: 7743

Asia WGS AF: 0.0300 AC: 107 AN: 3478

EpiCase AF: 0.0893

EpiControl AF: 0.0962

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	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	0.21
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Uncertain	0.060
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.72	D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D
MetaRNN	Benign	0.010	T
MetaSVM	Uncertain	-0.18	T
MutationAssessor	Pathogenic	3.4	M
PhyloP100		10
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-3.0	D
REVEL	Pathogenic	0.73
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0070	D
Polyphen		1.0	D
Vest4		0.33
MPC		0.37
ClinPred		0.061	T
GERP RS		5.7
Varity_R		0.89
gMVP		0.52
Mutation Taster		=26/74	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs33947968; hg19: chr10-26434455;