GeneBe

chrX-85878986-GAACA-G

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The ENST00000357749.7(CHM):​c.1584_1587delTGTT​(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
ENST00000357749.7 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:6O:1

Conservation

PhyloP100: 1.62

Publications

11 publications found
Variant links:
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 Gene-Disease associations (from GenCC):
  • choroideremia
    Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, G2P, ClinGen, Illumina

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 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 VariationId is 11152.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000357749.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected
GeneTranscriptTagsHGVScHGVSpEffectExon RankProteinUniProt
CHM
NM_000390.4
MANE Select
c.1584_1587delTGTTp.Val529HisfsTer7
frameshift
Exon 13 of 15NP_000381.1
CHM
NM_001320959.1
c.1140_1143delTGTTp.Val381HisfsTer7
frameshift
Exon 13 of 15NP_001307888.1
CHM
NM_001362517.1
c.1140_1143delTGTTp.Val381HisfsTer7
frameshift
Exon 13 of 15NP_001349446.1

Ensembl Transcripts

Selected
GeneTranscriptTagsHGVScHGVSpEffectExon RankProteinUniProt
CHM
ENST00000357749.7
TSL:1 MANE Select
c.1584_1587delTGTTp.Val529HisfsTer7
frameshift
Exon 13 of 15ENSP00000350386.2
CHM
ENST00000467744.2
TSL:5
n.127-15896_127-15893delTGTT
intron
N/A

Frequencies

GnomAD3 genomes
AF:
0.00000899
AC:
1
AN:
111237
Hom.:
0
Cov.:
22
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000189
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
9.24e-7
AC:
1
AN:
1082674
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
350314
show subpopulations
⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
African (AFR)
AF:
0.00
AC:
0
AN:
26136
American (AMR)
AF:
0.00
AC:
0
AN:
34986
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
19153
East Asian (EAS)
AF:
0.00
AC:
0
AN:
29956
South Asian (SAS)
AF:
0.00
AC:
0
AN:
53283
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
40292
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
3738
European-Non Finnish (NFE)
AF:
0.00000121
AC:
1
AN:
829613
Other (OTH)
AF:
0.00
AC:
0
AN:
45517
⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.275
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
GnomAD4 genome
AF:
0.00000899
AC:
1
AN:
111237
Hom.:
0
Cov.:
22
AF XY:
0.00
AC XY:
0
AN XY:
33513
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
30581
American (AMR)
AF:
0.00
AC:
0
AN:
10403
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
2640
East Asian (EAS)
AF:
0.00
AC:
0
AN:
3566
South Asian (SAS)
AF:
0.00
AC:
0
AN:
2677
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
5948
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
236
European-Non Finnish (NFE)
AF:
0.0000189
AC:
1
AN:
53011
Other (OTH)
AF:
0.00
AC:
0
AN:
1491
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.525
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Alfa
AF:
0.00
Hom.:
0
Bravo
AF:
0.00000378

ClinVar

ClinVar submissions as Germline

Significance:Pathogenic
Revision:criteria provided, multiple submitters, no conflicts
View on ClinVar
Pathogenic
VUS
Benign
Condition
3
-
-
Choroideremia (4)
2
-
-
not provided (2)
1
-
-
Retinal dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name
Calibrated prediction
Score
Prediction
PhyloP100
1.6
Mutation Taster
=4/196
disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs587776746; hg19: chrX-85133991; API