rs786204761

chrX-86027490-C-AchrX-86027490-C-T

Variant summary

Our verdict is Pathogenic. Variant got 22 ACMG points: 22P and 0B. PVS1 PM2 PP3_Strong PP5_Very_Strong

The NM_000390.4(CHM):c.116+1G>T variant causes a splice donor change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: CHM NM_000390.4 splice_donor
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3 O:1
• Conservation: PhyloP100: 5.79

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]

ACMG classification

Verdict is Pathogenic. Variant got 22 ACMG points.

• PVS1: Splicing variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant X-86027490-C-A is Pathogenic according to our data. Variant chrX-86027490-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 279770.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-86027490-C-A is described in Lovd as [Pathogenic]. Variant chrX-86027490-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHM	NM_000390.4	c.116+1G>T		splice_donor_variant		ENST00000357749.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHM	ENST00000357749.7	c.116+1G>T		splice_donor_variant		1	NM_000390.4	P1
CHM	ENST00000615443.1	c.116+1G>T		splice_donor_variant		1
CHM	ENST00000483950.1	n.146G>T		non_coding_transcript_exon_variant	2/2	3
CHM	ENST00000467744.2	n.126+1G>T		splice_donor_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 04, 2016	The CHM gene encodes Rab escort protein 1, a RAB geranylgeranyl transferase subunit necessary for the postranslational modification and membrane targeting of Rab proteins (van den Hurk et al., 2003). Pathogenic variants in the CHM gene cause choroideremia, an X-linked form of retinal dystrophy characterized by retinal pigment epithelium and photoreceptor degeneration with eventual complete choroid atrophy and bare sclera (van den Hurk et al., 1997; Guo et al., 2015; Sanchez-Alcudia et al., 2016). Affected males have night blindness, tunnel vision, and may eventually become completely blind (van den Hurk et al., 2003). Rarely, female carriers may be affected, but typically have only mild cone dysfunction, mottled irregularity of the fundus, and yellowish flecks in the macula over time (Cremers et al., 1990, van den Hurk et al., 1997, Renner et al., 2009). -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jun 01, 2022	For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 279770). Disruption of this splice site has been observed in individual(s) with choroideremia (PMID: 21905166, 27247961). This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 2 of the CHM gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in CHM are known to be pathogenic (PMID: 9067750, 23811034). -

Retinal dystrophy Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Blueprint Genetics

Jan 18, 2019

- -

Choroideremia Other:1

not provided, no classification provided

literature only

GeneReviews

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.71	D
BayesDel_noAF	Pathogenic	0.37
Cadd	Uncertain	25
Dann	Uncertain	1.0
FATHMM_MKL	Pathogenic	0.99	D
MutationTaster	Benign	1.0	D;D;D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.99		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs786204761; hg19: chrX-85282494;