X-85864672-C-A

Variant names:

• chrX-85864672-C-A
• rs748006115
• NM_000390.4:c.1920G>T

Variant summary

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

The NM_000390.4(CHM):​c.1920G>T​(p.Lys640Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000912 in 1,096,682 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: CHM NM_000390.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.00400

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=0.14161724).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHM	NM_000390.4	c.1920G>T	p.Lys640Asn	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.1920G>T	p.Lys640Asn	missense_variant	Exon 15 of 15	1	NM_000390.4	ENSP00000350386.2
CHM	ENST00000467744.2	n.127-1578G>T		intron_variant	Intron 2 of 2	5

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD3 exomes AF: 0.00000557 AC: 1 AN: 179599 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 64573

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: 0.0000542

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 9.12e-7 AC: 1 AN: 1096682 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 362356

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: 0.0000186

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	5.5
DANN	Uncertain	0.98
DEOGEN2	Benign	0.23	T
FATHMM_MKL	Benign	0.083	N
LIST_S2	Benign	0.60	T
M_CAP	Uncertain	0.090	D
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-0.54	T
MutationAssessor	Benign	1.8	L
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.80	N
REVEL	Benign	0.11
Sift	Benign	0.11	T
Sift4G	Benign	0.32	T
Polyphen		0.032	B
Vest4		0.075
MutPred		0.17		Loss of ubiquitination at K640 (P = 3e-04);
MVP		0.85
MPC		0.23
ClinPred		0.038	T
GERP RS		-0.71
Varity_R		0.11
gMVP		0.26

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: rs748006115; hg19: chrX-85119677; COSMIC: COSV100753053;