X-86027490-C-T

Position:

• chrX-86027490-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000390.4(CHM):​c.116+1G>A variant causes a splice donor, intron 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)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: CHM NM_000390.4 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7
• 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]

CHM (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) 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
• PP5: Variant X-86027490-C-T is Pathogenic according to our data. Variant chrX-86027490-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 189189.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-86027490-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHM	NM_000390.4	c.116+1G>A		splice_donor_variant, intron_variant		ENST00000357749.7	NP_000381.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHM	ENST00000357749.7	c.116+1G>A		splice_donor_variant, intron_variant		1	NM_000390.4	ENSP00000350386.2
CHM	ENST00000615443.1	c.116+1G>A		splice_donor_variant, intron_variant		1		ENSP00000484306.1
CHM	ENST00000483950.1	n.146G>A		non_coding_transcript_exon_variant	2/2	3
CHM	ENST00000467744.2	n.126+1G>A		splice_donor_variant, intron_variant		5

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1086437 Hom.: 0 Cov.: 27 AF XY: 0.00 AC XY: 0 AN XY: 353033

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	Jul 13, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 15, 2024	Canonical splice site variant predicted to result in a null allele 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, 25525159, 27596865, 10447648, 37734845) -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 03, 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: 189189). This variant is also known as 146+1G>A. Disruption of this splice site has been observed in individuals with clinical features of choroideremia (PMID: 10447648, 12827496, 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). -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -

Retinal dystrophy Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	Jan 01, 2009	- -
Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	May 07, 2018	- -

Choroideremia Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Counsyl

Feb 21, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.71	D
BayesDel_noAF	Pathogenic	0.35
CADD	Uncertain	25
DANN	Uncertain	0.99
FATHMM_MKL	Pathogenic	0.98	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; COSMIC: COSV62564414;