rs1555096070

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_000260.4(MYO7A):​c.4254delC​(p.Asp1419fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 33)

Consequence

MYO7A
NM_000260.4 frameshift

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2

Conservation

PhyloP100: 2.03
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]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 11-77194451-TC-T is Pathogenic according to our data. Variant chr11-77194451-TC-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 552398.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-77194451-TC-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
MYO7ANM_000260.4 linkuse as main transcriptc.4254delC p.Asp1419fs frameshift_variant 32/49 ENST00000409709.9 NP_000251.3 Q13402-1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
MYO7AENST00000409709.9 linkuse as main transcriptc.4254delC p.Asp1419fs frameshift_variant 32/491 NM_000260.4 ENSP00000386331.3 Q13402-1
MYO7AENST00000458637.6 linkuse as main transcriptc.4254delC p.Asp1419fs frameshift_variant 32/491 ENSP00000392185.2 Q13402-2
MYO7AENST00000409619.6 linkuse as main transcriptc.4221delC p.Asp1408fs frameshift_variant 33/501 ENSP00000386635.2 Q13402-8
MYO7AENST00000458169.2 linkuse as main transcriptc.1797delC p.Asp600fs frameshift_variant 12/291 ENSP00000417017.2 H7C4D8
MYO7AENST00000670577.1 linkuse as main transcriptn.2094delC non_coding_transcript_exon_variant 15/32 ENSP00000499323.1 A0A590UJ94

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
30
GnomAD4 genome
Cov.:
33
Bravo
AF:
0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Usher syndrome type 1;C1838701:Autosomal recessive nonsyndromic hearing loss 2 Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingCounsylJun 19, 2017- -
not provided Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpAug 10, 2023This sequence change creates a premature translational stop signal (p.Asp1419Thrfs*7) in the MYO7A gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MYO7A are known to be pathogenic (PMID: 8900236, 25404053). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with Usher syndrome (PMID: 26338283). This variant is also known as c.4251delC (p.I1417fs). ClinVar contains an entry for this variant (Variation ID: 552398). For these reasons, this variant has been classified as Pathogenic. -

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.

Other links and lift over

dbSNP: rs1555096070; hg19: chr11-76905496; API