Genetic Variant CHM:p.Cys499* (chrX-85894201-G-T) – ACMG Classification: Pathogenic (12 pts)

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate

The NM_000390.4(CHM):c.1497C>A(p.Cys499*) variant causes a stop gained change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. C499C) has been classified as Uncertain significance. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 23)

Consequence

CHM
NM_000390.4 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 4.17

Publications

2 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: G2P, Orphanet, Illumina, Labcorp Genetics (formerly Invitae), ClinGen

CHM links:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 12 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-85894201-G-T is Pathogenic according to our data. Variant chrX-85894201-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 11153.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000390.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CHM	NM_000390.4	MANE Select	c.1497C>A	p.Cys499*	stop_gained	Exon 12 of 15	NP_000381.1	P24386-1
CHM	NM_001320959.1		c.1053C>A	p.Cys351*	stop_gained	Exon 12 of 15	NP_001307888.1	B4DRL9
CHM	NM_001362517.1		c.1053C>A	p.Cys351*	stop_gained	Exon 12 of 15	NP_001349446.1	B4DRL9

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CHM	ENST00000357749.7	TSL:1 MANE Select	c.1497C>A	p.Cys499*	stop_gained	Exon 12 of 15	ENSP00000350386.2	P24386-1
CHM	ENST00000891168.1		c.1494C>A	p.Cys498*	stop_gained	Exon 12 of 15	ENSP00000561227.1
CHM	ENST00000891170.1		c.1497C>A	p.Cys499*	stop_gained	Exon 12 of 15	ENSP00000561229.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Choroideremia (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.71

BayesDel_noAF

Pathogenic

0.62

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

FATHMM_MKL

Pathogenic

0.98

PhyloP100

4.2

Vest4

0.99

GERP RS

4.1

Mutation Taster

=1/199

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over