rs886043716
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000390.4(CHM):c.649_652del(p.Tyr217HisfsTer14) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. Y217Y) has been classified as Benign. Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 23)
Consequence
CHM
NM_000390.4 frameshift
NM_000390.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 7.91
Genes affected
CHM (HGNC:1940): (CHM Rab escort protein) This gene encodes component A of the RAB geranylgeranyl transferase holoenzyme. In the dimeric holoenzyme, this subunit binds unprenylated Rab GTPases and then presents them to the catalytic Rab GGTase subunit for the geranylgeranyl transfer reaction. Rab GTPases need to be geranylgeranyled on either one or two cysteine residues in their C-terminus to localize to the correct intracellular membrane. Mutations in this gene are a cause of choroideremia; also known as tapetochoroidal dystrophy (TCD). This X-linked disease is characterized by progressive dystrophy of the choroid, retinal pigment epithelium and retina. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Mar 2016]
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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 X-85963714-GAGTA-G is Pathogenic according to our data. Variant chrX-85963714-GAGTA-G is described in ClinVar as [Pathogenic]. Clinvar id is 287749.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-85963714-GAGTA-G is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CHM | NM_000390.4 | c.649_652del | p.Tyr217HisfsTer14 | frameshift_variant | 5/15 | ENST00000357749.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CHM | ENST00000357749.7 | c.649_652del | p.Tyr217HisfsTer14 | frameshift_variant | 5/15 | 1 | NM_000390.4 | P1 | |
CHM | ENST00000467744.2 | n.126+63773_126+63776del | intron_variant, non_coding_transcript_variant | 5 |
Frequencies
GnomAD3 genomes ? Cov.: 23
GnomAD3 genomes
?
Cov.:
23
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome ? Cov.: 23
GnomAD4 genome
?
Cov.:
23
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jun 04, 2016 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 08, 2022 | For these reasons, this variant has been classified as Pathogenic. This premature translational stop signal has been observed in individual(s) with choroideremia (PMID: 23811034). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Tyr217Hisfs*14) in the CHM gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CHM are known to be pathogenic (PMID: 9067750, 23811034). - |
Computational scores
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Calibrated prediction
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Prediction
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at