X-85864731-A-T

Variant names:

• chrX-85864731-A-T
• NM_000390.4:c.1861T>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000390.4(CHM):​c.1861T>A​(p.Leu621Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: CHM NM_000390.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0230

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.077706605).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHM	NM_000390.4	c.1861T>A	p.Leu621Ile	missense_variant	Exon 15 of 15	ENST00000357749.7	NP_000381.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHM	ENST00000357749.7	c.1861T>A	p.Leu621Ile	missense_variant	Exon 15 of 15	1	NM_000390.4	ENSP00000350386.2
CHM	ENST00000467744.2	n.127-1637T>A		intron_variant	Intron 2 of 2	5

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Aug 31, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces leucine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 621 of the CHM protein (p.Leu621Ile). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with CHM-related conditions. Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt CHM protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	6.8
DANN	Benign	0.92
DEOGEN2	Benign	0.13	T
FATHMM_MKL	Benign	0.027	N
LIST_S2	Benign	0.19	T
M_CAP	Benign	0.035	D
MetaRNN	Benign	0.078	T
MetaSVM	Benign	-0.65	T
MutationAssessor	Benign	1.3	L
PrimateAI	Benign	0.26	T
PROVEAN	Benign	0.0	N
REVEL	Benign	0.062
Sift	Benign	0.20	T
Sift4G	Benign	0.19	T
Polyphen		0.0020	B
Vest4		0.13
MutPred		0.23		Gain of catalytic residue at P623 (P = 0.0337);
MVP		0.72
MPC		0.22
ClinPred		0.049	T
GERP RS		0.43
Varity_R		0.10
gMVP		0.12

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

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-85119736; COSMIC: COSV100753505;