NM_000390.4:c.280delA

Variant names:

• chrX-85978800-GT-G
• rs1555958073
• NM_000390.4:c.280delA

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_000390.4(CHM):​c.280delA​(p.Thr94LeufsTer32) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 23)
• Consequence: CHM NM_000390.4 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 3.28

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 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-85978800-GT-G is Pathogenic according to our data. Variant chrX-85978800-GT-G is described in ClinVar as [Pathogenic]. Clinvar id is 440813.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHM	NM_000390.4	c.280delA	p.Thr94LeufsTer32	frameshift_variant	Exon 4 of 15	ENST00000357749.7	NP_000381.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHM	ENST00000357749.7	c.280delA	p.Thr94LeufsTer32	frameshift_variant	Exon 4 of 15	1	NM_000390.4	ENSP00000350386.2
CHM	ENST00000615443.1	c.280delA	p.Thr94LeufsTer20	frameshift_variant	Exon 4 of 5	1		ENSP00000484306.1
CHM	ENST00000487515.1	n.164delA		non_coding_transcript_exon_variant	Exon 2 of 2	5
CHM	ENST00000467744.2	n.126+48690delA		intron_variant	Intron 2 of 2	5

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Choroideremia Pathogenic:1

May 11, 2016

Hunan Clinical Research Center of Ophthalmic Disease, The Second Xiangya Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

Affected subject presented with serious chorioretinal atrophy, pigment proliferation, shallower anterior chambers, angle closed and high intraocular pressure (IOP). -

Computational scores

Source: dbNSFP v4.3

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

LitVar

Other links and lift over

dbSNP: rs1555958073; hg19: chrX-85233804;