rs111033232

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2PM4_SupportingPP5_Very_Strong

The NM_000260.4(MYO7A):c.5886_5888delCTT(p.Phe1963del) variant causes a disruptive inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000248 in 1,613,408 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000024 ( 0 hom. )

Consequence

MYO7A
NM_000260.4 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 7.67

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 Pathogenic. Variant got 11 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM4

Nonframeshift variant in NON repetitive region in NM_000260.4. Strenght limited to Supporting due to length of the change: 1aa.

PP5

Variant 11-77208452-ACTT-A is Pathogenic according to our data. Variant chr11-77208452-ACTT-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 43308.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-77208452-ACTT-A is described in Lovd as [Pathogenic]. Variant chr11-77208452-ACTT-A is described in Lovd as [Likely_pathogenic]. Variant chr11-77208452-ACTT-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYO7A	NM_000260.4 link	c.5886_5888delCTT	p.Phe1963del	disruptive_inframe_deletion	Exon 43 of 49	ENST00000409709.9	NP_000251.3	Q13402-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
MYO7A	ENST00000409709.9 link	c.5886_5888delCTT	p.Phe1963del	disruptive_inframe_deletion	Exon 43 of 49	1	NM_000260.4	ENSP00000386331.3	Q13402-1
MYO7A	ENST00000458637.6 link	c.5772_5774delCTT	p.Phe1925del	disruptive_inframe_deletion	Exon 43 of 49	1		ENSP00000392185.2	Q13402-2
MYO7A	ENST00000409619.6 link	c.5739_5741delCTT	p.Phe1914del	disruptive_inframe_deletion	Exon 44 of 50	1		ENSP00000386635.2	Q13402-8
MYO7A	ENST00000458169.2 link	c.3312_3314delCTT	p.Phe1105del	disruptive_inframe_deletion	Exon 23 of 29	1		ENSP00000417017.2	H7C4D8
MYO7A	ENST00000670577.1 link	n.484_486delCTT		non_coding_transcript_exon_variant	Exon 26 of 32			ENSP00000499323.1	A0A590UJ94
MYO7A	ENST00000670577 link	n.484_486delCTT		3_prime_UTR_variant	Exon 26 of 30			ENSP00000499323.1	A0A590UJ94

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152146

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

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:

0.000189

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000402

AC:

AN:

248662

Hom.:

AF XY:

0.0000222

AC XY:

AN XY:

134962

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000167

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000139

Gnomad NFE exome

AF:

0.0000177

Gnomad OTH exome

AF:

0.000331

GnomAD4 exome

AF:

0.0000240

AC:

AN:

1461262

Hom.:

AF XY:

0.0000193

AC XY:

AN XY:

726900

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.000187

Gnomad4 NFE exome

AF:

0.0000162

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000329

AC:

AN:

152146

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74316

show subpopulations

Gnomad4 AFR

AF:

0.0000482

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000189

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000540

Hom.:

Bravo

AF:

0.0000151

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Usher syndrome type 1

Pathogenic:3

Jan 03, 2022

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000043308, PMID:16679490).It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000043, PM2_M). This inframe deletion in the non-repeat region can change the length of the protein and disrupt protein function (PM4_M). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least 2 similarly affected unrelated individuals(PMID: 16679490, 30459346, 29142287, PM3_S). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -

Mar 25, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 08, 2021

Ocular Genomics Institute, Massachusetts Eye and Ear

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

The MYO7A c.5886_5888del variant was identified in an individual with retinitis pigmentosa with a presumed recessive inheritance pattern. Through a review of available evidence we were able to apply the following criteria: PVS1, PM2, PP1, PM3. Based on this evidence we have classified this variant as Pathogenic. -

Autosomal recessive nonsyndromic hearing loss 2

Pathogenic:1

Apr 01, 2023

Clinical Laboratory Sciences Program (CLSP), King Saud bin Abdulaziz University for Health Sciences (KSAU-HS)

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Usher syndrome type 1B

Pathogenic:1

Apr 01, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided

Pathogenic:1

Jul 23, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant, c.5886_5888del, results in the deletion of 1 amino acid(s) of the MYO7A protein (p.Phe1963del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs745646247, gnomAD 0.02%). This variant has been observed in individual(s) with autosomal recessive Usher syndrome (PMID: 16679490, 24199935, 29142287, 30459346, 31479088). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as p.Phe1962del. ClinVar contains an entry for this variant (Variation ID: 43308). For these reasons, this variant has been classified as Pathogenic. -

Rare genetic deafness

Pathogenic:1

Mar 08, 2011

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The Phe1963del variant in MYO7A has been previously reported in the literature i n three individual with clinical features of Usher syndrome and was not identifi ed in 352 control chromosomes (Roux 2006, Baux 2008 ? unpublished data from the UMD database). Two of these individuals had a second MYO7A variant and one indiv idual was homozygous for this variant. In addition, our laboratory has detected this variant as a compound heterozygous variant in two sets of affected siblings . The Phe1963del variant is predicted to cause an inframe deletion, which alters the protein's amino acid sequence by removing the phenylalanine amino acid at p osition 1963. In summary, this variant meets our criteria to be classified as pa thogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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