X-85864685-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_000390.4(CHM):c.1907C>T(p.Ser636Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000662 in 1,207,834 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. S636S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000090 (0 hom., 0 hem., cov: 23)
  • Exomes 𝑓: 0.0000064 (0 hom. 3 hem.)
• Consequence: CHM NM_000390.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.12

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_benign. Variant got -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.18949777).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHM	NM_000390.4	c.1907C>T	p.Ser636Leu	missense_variant	15/15	ENST00000357749.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHM	ENST00000357749.7	c.1907C>T	p.Ser636Leu	missense_variant	15/15	1	NM_000390.4	P1
CHM	ENST00000467744.2	n.127-1591C>T		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.00000898 AC: 1 AN: 111343 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 33529

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000188

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000558 AC: 1 AN: 179238 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 64240

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000638 AC: 7 AN: 1096491 Hom.: 0 Cov.: 29 AF XY: 0.00000829 AC XY: 3 AN XY: 362073

Gnomad4 AFR exome AF: 0.0000379

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000186

Gnomad4 FIN exome AF: 0.0000247

Gnomad4 NFE exome AF: 0.00000476

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000898 AC: 1 AN: 111343 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 33529

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000188

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 30, 2021

This sequence change replaces serine with leucine at codon 636 of the CHM protein (p.Ser636Leu). The serine residue is weakly conserved and there is a large physicochemical difference between serine and leucine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with CHM-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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	0.070
BayesDel_addAF	Benign	-0.063	T
BayesDel_noAF	Benign	-0.33
Cadd	Benign	15
Dann	Benign	0.96
DEOGEN2	Benign	0.31	T
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.73	T
M_CAP	Benign	0.055	D
MetaRNN	Benign	0.19	T
MetaSVM	Uncertain	0.012	D
MutationAssessor	Benign	1.4	L
MutationTaster	Benign	0.67	N;N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.24
Sift	Benign	0.34	T
Sift4G	Benign	0.31	T
Polyphen		0.0020	B
Vest4		0.11
MutPred		0.24		Loss of phosphorylation at S636 (P = 0.0172);
MVP		0.79
MPC		0.25
ClinPred		0.29	T
GERP RS		4.9
Varity_R		0.27
gMVP		0.35

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: rs1181669285; hg19: chrX-85119690;