rs200359303

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBP6

The NM_000260.4(MYO7A):c.6615G>A(p.Met2205Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0001 in 1,588,180 control chromosomes in the GnomAD database, including 1 homozygotes. 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 0.00035 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000074 ( 1 hom. )

Consequence

MYO7A
NM_000260.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: 6.51

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 Likely_benign. Variant got -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.033611804).

BP6

Variant 11-77214663-G-A is Benign according to our data. Variant chr11-77214663-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 164726.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYO7A	NM_000260.4 linkuse as main transcript	c.6615G>A	p.Met2205Ile	missense_variant	49/49	ENST00000409709.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYO7A	ENST00000409709.9 linkuse as main transcript	c.6615G>A	p.Met2205Ile	missense_variant	49/49	1	NM_000260.4		Q13402-1

Frequencies

GnomAD3 genomes

AF:

0.000342

AC:

AN:

152214

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00118

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000105

AC:

AN:

208946

Hom.:

AF XY:

0.0000893

AC XY:

AN XY:

112018

show subpopulations

Gnomad AFR exome

AF:

0.00166

Gnomad AMR exome

AF:

0.0000336

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000392

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000738

AC:

106

AN:

1435848

Hom.:

Cov.:

AF XY:

0.0000731

AC XY:

AN XY:

711382

show subpopulations

Gnomad4 AFR exome

AF:

0.00273

Gnomad4 AMR exome

AF:

0.0000246

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000245

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.000202

GnomAD4 genome

AF:

0.000348

AC:

AN:

152332

Hom.:

Cov.:

AF XY:

0.000295

AC XY:

AN XY:

74484

show subpopulations

Gnomad4 AFR

AF:

0.00120

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000344

Hom.:

Bravo

AF:

0.000423

ESP6500AA

AF:

0.000982

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000108

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Feb 25, 2020	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Sep 08, 2013

Variant classified as Uncertain Significance - Favor Benign. The Met2205Ile vari ant in MYO7A has not been reported in individuals with hearing loss, but has bee n identified in 0.1% (4/4072) of African American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs200359303). Alth ough this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. Computational analyses (biochemical a mino acid properties, conservation, AlignGVGD, PolyPhen2, and SIFT) suggest that the Met2205Ile variant may not impact the protein, though this information is n ot predictive enough to rule out pathogenicity. In summary, the clinical signifi cance of this variant cannot be determined with certainty; however based upon th e computational data and the presence of the variant in the general population, we would lean towards a more likely benign role. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.63

BayesDel_addAF

Benign

-0.084

BayesDel_noAF

Uncertain

0.10

Cadd

Uncertain

Dann

Uncertain

0.99

DEOGEN2

Uncertain

0.48

T;.;.;T

Eigen

Uncertain

0.19

Eigen_PC

Uncertain

0.33

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.94

D;D;D;D

M_CAP

Uncertain

0.16

MetaRNN

Benign

0.034

T;T;T;T

MetaSVM

Uncertain

0.025

MutationAssessor

Uncertain

2.3

M;.;.;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.59

PROVEAN

Uncertain

-2.5

N;N;N;N

REVEL

Uncertain

0.53

Sift

Benign

0.10

T;T;T;T

Sift4G

Benign

0.17

T;T;T;T

Polyphen

0.026

B;.;.;.

Vest4

0.44

MutPred

0.29

Loss of disorder (P = 0.0375);.;.;.;

MVP

0.83

MPC

0.12

ClinPred

0.059

GERP RS

5.5

Varity_R

0.60

gMVP

0.54

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

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