rs397514603

Variant names:

• chrX-85879054-T-C
• rs397514603
• NM_000390.4:c.1520A>G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_000390.4(CHM):​c.1520A>G​(p.His507Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000000937 in 1,067,739 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 9.4e-7 (0 hom. 1 hem.)
• Consequence: CHM NM_000390.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 5.00

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 Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.957
• PP5: Variant X-85879054-T-C is Pathogenic according to our data. Variant chrX-85879054-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 39809.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chrX-85879054-T-C is described in Lovd as [Pathogenic]. Variant chrX-85879054-T-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHM	NM_000390.4	c.1520A>G	p.His507Arg	missense_variant	Exon 13 of 15	ENST00000357749.7	NP_000381.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHM	ENST00000357749.7	c.1520A>G	p.His507Arg	missense_variant	Exon 13 of 15	1	NM_000390.4	ENSP00000350386.2
CHM	ENST00000467744.2	n.127-15960A>G		intron_variant	Intron 2 of 2	5

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 9.37e-7 AC: 1 AN: 1067739 Hom.: 0 Cov.: 26 AF XY: 0.00000298 AC XY: 1 AN XY: 336059

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000222

GnomAD4 genome Cov.: 23

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Choroideremia Pathogenic:2

Jan 04, 2024

3billion

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is not observed in the gnomAD v2.1.1 dataset. Predicted Consequence/Location: The majority of the known disease-causing variants of this gene are variants expected to result in premature termination of the protein. Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 21905166). In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.75 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.70 (>=0.6, sensitivity 0.72 and precision 0.9)]. Same nucleotide change resulting in same amino acid change has been previously reported to be associated with CHM related disorder (ClinVar ID: VCV000039809 /PMID: 21905166). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline. -

Dec 01, 2011

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.54
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.97	D
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.95	D
M_CAP	Uncertain	0.19	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Uncertain	0.41	D
MutationAssessor	Pathogenic	3.6	H
PrimateAI	Uncertain	0.63	T
PROVEAN	Pathogenic	-7.0	D
REVEL	Pathogenic	0.75
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.95
MutPred		0.78		Gain of MoRF binding (P = 0.0184);
MVP		1.0
MPC		0.85
ClinPred		1.0	D
GERP RS		2.8
Varity_R		0.98
gMVP		0.93

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: rs397514603; hg19: chrX-85134059;