rs587776746
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000390.4(CHM):c.1584_1587del(p.Val529HisfsTer7) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000168 in 1,193,911 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.0000090 ( 0 hom., 0 hem., cov: 22)
Exomes 𝑓: 9.2e-7 ( 0 hom. 0 hem. )
Consequence
CHM
NM_000390.4 frameshift
NM_000390.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 1.62
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]
Genome browser will be placed here
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-85878986-GAACA-G is Pathogenic according to our data. Variant chrX-85878986-GAACA-G is described in ClinVar as [Pathogenic]. Clinvar id is 11152.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-85878986-GAACA-G is described in Lovd as [Pathogenic]. Variant chrX-85878986-GAACA-G is described in Lovd as [Pathogenic]. Variant chrX-85878986-GAACA-G is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CHM | NM_000390.4 | c.1584_1587del | p.Val529HisfsTer7 | frameshift_variant | 13/15 | ENST00000357749.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CHM | ENST00000357749.7 | c.1584_1587del | p.Val529HisfsTer7 | frameshift_variant | 13/15 | 1 | NM_000390.4 | P1 | |
CHM | ENST00000467744.2 | n.127-15896_127-15893del | intron_variant, non_coding_transcript_variant | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.00000899 AC: 1AN: 111237Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0AN XY: 33513
GnomAD3 genomes
?
AF:
AC:
1
AN:
111237
Hom.:
Cov.:
22
AF XY:
AC XY:
0
AN XY:
33513
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD4 exome AF: 9.24e-7 AC: 1AN: 1082674Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 350314
GnomAD4 exome
AF:
AC:
1
AN:
1082674
Hom.:
AF XY:
AC XY:
0
AN XY:
350314
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome ? AF: 0.00000899 AC: 1AN: 111237Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0AN XY: 33513
GnomAD4 genome
?
AF:
AC:
1
AN:
111237
Hom.:
Cov.:
22
AF XY:
AC XY:
0
AN XY:
33513
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
Bravo
AF:
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:5Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Choroideremia Pathogenic:2Other:1
Pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Feb 02, 2022 | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as a Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Choroideremia (MIM# 303100). (I) 0110 - This gene is associated with X-linked disease. Males are predominantly affected, while females are usually unaffected some may display symptoms similar to affected males due to random X-inactivation (PMID: 29555028). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v3) <0.001 for a dominant condition (1 heterozygote, 0 homozygotes, hemizygotes). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (ClinVar). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported in multiple individuals with choroideremia (ClinVar, PMID: 27739455, 33110609). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Aug 01, 2014 | - - |
not provided, no classification provided | literature only | GeneReviews | - | - - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 04, 2024 | This sequence change creates a premature translational stop signal (p.Val529Hisfs*7) 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). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with clinical features of choroideremia (PMID: 25912515, 30541579, 31181178). ClinVar contains an entry for this variant (Variation ID: 11152). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | May 26, 2023 | Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 31922496, 18087237, 1598901, 25912515, 28752371, 30541579, 27739455, 31097864, 35040292, 33573424, 27936069, 24913019, 12203991, 33110609, 8242078) - |
Retinal dystrophy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Blueprint Genetics | Apr 25, 2019 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at