X-85900700-GG-CT

Variant names:

• chrX-85900700-GG-CT
• NM_000390.4:c.1358_1359delCCinsAG
• CHM p.Ser453*

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PVS1

The NM_000390.4(CHM):​c.1358_1359delCCinsAG​(p.Ser453*) variant causes a stop gained change. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. S453S) has been classified as Likely pathogenic. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 22)
• Consequence: CHM NM_000390.4 stop_gained
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.16
• Publications: 0 publications found

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

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHM	NM_000390.4	MANE Select	c.1358_1359delCCinsAG	p.Ser453*	stop_gained	N/A	NP_000381.1	P24386-1
	CHM	NM_001320959.1		c.914_915delCCinsAG	p.Ser305*	stop_gained	N/A	NP_001307888.1	B4DRL9
	CHM	NM_001362517.1		c.914_915delCCinsAG	p.Ser305*	stop_gained	N/A	NP_001349446.1	B4DRL9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHM	ENST00000357749.7	TSL:1 MANE Select	c.1358_1359delCCinsAG	p.Ser453*	stop_gained	N/A	ENSP00000350386.2	P24386-1
	CHM	ENST00000891168.1		c.1355_1356delCCinsAG	p.Ser452*	stop_gained	N/A	ENSP00000561227.1
	CHM	ENST00000891170.1		c.1358_1359delCCinsAG	p.Ser453*	stop_gained	N/A	ENSP00000561229.1

Frequencies

GnomAD3 genomes Cov.: 22

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 22

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		4.2

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chrX-85155705;