rs375253473

Positions:

chr11-77179070-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_000260.4(MYO7A):c.2308G>A(p.Ala770Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000134 in 1,608,702 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00014 ( 0 hom. )

Consequence

MYO7A
NM_000260.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:1

Conservation

PhyloP100: 1.98

Variant links:

Genes affected

MYO7A (HGNC:7606): (myosin VIIA) This gene is a member of the myosin gene family. Myosins are mechanochemical proteins characterized by the presence of a motor domain, an actin-binding domain, a neck domain that interacts with other proteins, and a tail domain that serves as an anchor. This gene encodes an unconventional myosin with a very short tail. Defects in this gene are associated with the mouse shaker-1 phenotype and the human Usher syndrome 1B which are characterized by deafness, reduced vestibular function, and (in human) retinal degeneration. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2008]

MYO7A links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.1475566).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYO7A	NM_000260.4 linkuse as main transcript	c.2308G>A	p.Ala770Thr	missense_variant	20/49	ENST00000409709.9	NP_000251.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYO7A	ENST00000409709.9 linkuse as main transcript	c.2308G>A	p.Ala770Thr	missense_variant	20/49	1	NM_000260.4	ENSP00000386331		Q13402-1

Frequencies

GnomAD3 genomes

AF:

0.0000723

AC:

AN:

152244

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000770

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000108

AC:

AN:

241424

Hom.:

AF XY:

0.000114

AC XY:

AN XY:

131410

show subpopulations

Gnomad AFR exome

AF:

0.0000689

Gnomad AMR exome

AF:

0.0000294

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000452

Gnomad SAS exome

AF:

0.0000340

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000138

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000140

AC:

204

AN:

1456458

Hom.:

Cov.:

AF XY:

0.000145

AC XY:

105

AN XY:

723988

show subpopulations

Gnomad4 AFR exome

AF:

0.0000898

Gnomad4 AMR exome

AF:

0.0000226

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000177

Gnomad4 SAS exome

AF:

0.0000352

Gnomad4 FIN exome

AF:

0.0000193

Gnomad4 NFE exome

AF:

0.000166

Gnomad4 OTH exome

AF:

0.0000498

GnomAD4 genome

AF:

0.0000723

AC:

AN:

152244

Hom.:

Cov.:

AF XY:

0.0000807

AC XY:

AN XY:

74370

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000770

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000103

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000654

Hom.:

Bravo

AF:

0.0000945

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000355

AC:

ExAC

AF:

0.000116

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jul 29, 2022	Identified with additional MYO7A variants in a patient with mild adult-onset hearing loss in published literature (Ji et al., 2014); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25342930) -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 28, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 30, 2022	The p.Ala770Thr variant in MYO7A has been reported in 1 Asian individual with adult-onset hearing loss (Ji 2014 PMID: 25342930) and has been identified by our laboratory in 1 Asian individual with features of Usher syndrome who carried pathogenic variants in another gene that were sufficient to explain their disease (LMM data). It has also been identified in 0.06% (11/19272) of East Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org). However, this frequency is low enough to be consistent with a recessive allele frequency. This variant has also been reported in ClinVar (Variation ID 229002). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, while the clinical significance of this variant is uncertain, these data suggest that it is more likely to be benign. ACMG/AMP Criteria applied: BP5. -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jan 23, 2018	The p.Ala770Thr variant (rs375253473) has not been reported in the medical literature; however a similar nearby variant (p.Ala771Ser) has been reported in two patients with Usher type I syndrome, one of whom carried a second PCDH15 variant (Nakanishi 2010 and Yoshimura 2014). This variant is listed in the Genome Aggregation Database (gnomAD) with a frequency of 0.05 percent in the East Asian population (identified on 10 out of 18,616 chromosomes), and has been reported to the ClinVar database with an uncertain classification (Variation ID: 229002). The alanine at position 770 is moderately conserved considering 13 species and computational analyses of the effects of the p.Ala770Thr variant on protein structure and function provide conflicting results (SIFT: damaging, MutationTaster: polymorphism, PolyPhen-2: possibly damaging). Altogether, there is not enough evidence to classify the p.Ala770Thr variant with certainty. -

Usher syndrome type 1B

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Natera, Inc.

Feb 02, 2020

- -

Usher syndrome type 1;C1832475:Autosomal dominant nonsyndromic hearing loss 11;C1838701:Autosomal recessive nonsyndromic hearing loss 2

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Dec 30, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.33

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.38

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.45

T;T;.;.;.

Eigen

Uncertain

0.23

Eigen_PC

Benign

0.11

FATHMM_MKL

Uncertain

0.80

LIST_S2

Uncertain

0.94

D;D;D;D;D

M_CAP

Benign

0.060

MetaRNN

Benign

0.15

T;T;T;T;T

MetaSVM

Benign

-0.69

MutationAssessor

Pathogenic

3.2

M;.;M;.;.

MutationTaster

Benign

1.0

N;N;N;N

PrimateAI

Uncertain

0.48

PROVEAN

Uncertain

-2.8

D;.;D;D;.

REVEL

Benign

0.26

Sift

Uncertain

0.0020

D;.;D;D;.

Sift4G

Benign

0.076

T;D;T;T;.

Polyphen

0.92

P;.;.;.;.

Vest4

0.54

MVP

0.74

MPC

0.21

ClinPred

0.38

GERP RS

4.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.53

gMVP

0.56

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over