rs1472566324

Positions:

chr11-77156676-G-A

Variant summary

Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PS1PM1PM2PP3_StrongPP5_Very_Strong

The NM_000260.4(MYO7A):c.487G>A(p.Gly163Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000372 in 1,613,778 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin Lovd.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

MYO7A
NM_000260.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: 9.99

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:

MYO7A (HGNC:):

MYO7A links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 20 ACMG points.

PS1

Transcript NM_000260.4 (MYO7A) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in Lovd

PM1

In a binding_site (size 7) in uniprot entity MYO7A_HUMAN there are 7 pathogenic changes around while only 0 benign (100%) in NM_000260.4

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.991

PP5

Variant 11-77156676-G-A is Pathogenic according to our data. Variant chr11-77156676-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 553070.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-77156676-G-A is described in Lovd as [Likely_pathogenic]. Variant chr11-77156676-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYO7A	NM_000260.4 linkuse as main transcript	c.487G>A	p.Gly163Arg	missense_variant	6/49	ENST00000409709.9	NP_000251.3	Q13402-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
MYO7A	ENST00000409709.9 linkuse as main transcript	c.487G>A	p.Gly163Arg	missense_variant	6/49	1	NM_000260.4	ENSP00000386331.3	Q13402-1
MYO7A	ENST00000458637.6 linkuse as main transcript	c.487G>A	p.Gly163Arg	missense_variant	6/49	1		ENSP00000392185.2	Q13402-2
MYO7A	ENST00000409619.6 linkuse as main transcript	c.454G>A	p.Gly152Arg	missense_variant	7/50	1		ENSP00000386635.2	Q13402-8

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152164

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00000401

AC:

AN:

249206

Hom.:

AF XY:

0.00000740

AC XY:

AN XY:

135212

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000342

AC:

AN:

1461614

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

727086

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152164

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74346

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

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

Bravo

AF:

0.00000756

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 02, 2024	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 163 of the MYO7A protein (p.Gly163Arg). This variant is present in population databases (no rsID available, gnomAD 0.004%). This missense change has been observed in individual(s) with autosomal recessive Usher syndrome and autosomal recessive deafness (PMID: 16679490, 21873662, 26561413, 27583663, 31479088). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 553070). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MYO7A protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 17, 2022	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: 32864763, 27583663, 31479088, 26561413, 16679490, 26969326, 21436283, 33089500, 21873662) -

Retinal dystrophy

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	Jan 01, 2021	- -
Pathogenic, criteria provided, single submitter	research	Ophthalmic Genetics Group, Institute of Molecular and Clinical Ophthalmology Basel	May 27, 2024	- -

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

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Counsyl

Aug 01, 2017

- -

Usher syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

May 12, 2023

Variant summary: MYO7A c.487G>A (p.Gly163Arg) results in a non-conservative amino acid change located in the Myosin head, motor domain (IPR001609) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 249206 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.487G>A has been reported in the literature in multiple homozygous and compound heterozygous individuals affected with Usher Syndrome (e.g., Roux_2006, Atik_2015, Bouzidi_2022). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 26561413, 35551639, 21436283). Five ClinVar submitters (evaluation after 2014) have cited the variant, and all laboratories classified the variant as pathogenic (n = 3) or likely pathogenic (n = 2). Based on the evidence outlined above, the variant was classified as pathogenic. -

Usher syndrome type 1B

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Natera, Inc.

Jan 21, 2020

- -

Usher syndrome type 1

Pathogenic:1

Pathogenic, no assertion criteria provided

research

Department of Biotechnology and Genetic Engineering, Kohat University of Science and Technology

Aug 22, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.47

BayesDel_noAF

Pathogenic

0.54

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.96

D;D;.;.

Eigen

Pathogenic

0.99

Eigen_PC

Pathogenic

0.85

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

D;D;D;D

M_CAP

Pathogenic

0.51

MetaRNN

Pathogenic

0.99

D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.1

H;.;H;.

PrimateAI

Pathogenic

0.93

PROVEAN

Pathogenic

-6.5

D;.;D;D

REVEL

Pathogenic

0.97

Sift

Pathogenic

0.0

D;.;D;D

Sift4G

Uncertain

0.0020

D;D;D;D

Polyphen

1.0

D;.;.;.

Vest4

0.96

MutPred

0.96

Gain of methylation at K164 (P = 0.0738);Gain of methylation at K164 (P = 0.0738);Gain of methylation at K164 (P = 0.0738);.;

MVP

0.98

MPC

0.51

ClinPred

1.0

GERP RS

5.0

Varity_R

0.93

gMVP

0.94

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