chrX-85864687-G-T

Variant names:

• chrX-85864687-G-T
• rs772394005
• NM_000390.4:c.1905C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000390.4(CHM):​c.1905C>A​(p.Asn635Lys) 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. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.0000018 (0 hom. 1 hem.)
  • Failed GnomAD Quality Control
• Consequence: CHM NM_000390.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.479
• Publications: 0 publications found

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]

CHM Gene-Disease associations (from GenCC):

• choroideremia

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Illumina, Labcorp Genetics (formerly Invitae), ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07551712).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000390.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHM	NM_000390.4	MANE Select	c.1905C>A	p.Asn635Lys	missense	Exon 15 of 15	NP_000381.1	P24386-1
	CHM	NM_001320959.1		c.1461C>A	p.Asn487Lys	missense	Exon 15 of 15	NP_001307888.1	B4DRL9
	CHM	NM_001362517.1		c.1461C>A	p.Asn487Lys	missense	Exon 15 of 15	NP_001349446.1	B4DRL9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHM	ENST00000357749.7	TSL:1 MANE Select	c.1905C>A	p.Asn635Lys	missense	Exon 15 of 15	ENSP00000350386.2	P24386-1
	CHM	ENST00000891168.1		c.1902C>A	p.Asn634Lys	missense	Exon 15 of 15	ENSP00000561227.1
	CHM	ENST00000891170.1		c.1890C>A	p.Asn630Lys	missense	Exon 15 of 15	ENSP00000561229.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD2 exomes AF: 0.0000112 AC: 2 AN: 179191 AF XY: 0.0000156

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000147

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000182 AC: 2 AN: 1096549 Hom.: 0 Cov.: 29 AF XY: 0.00000276 AC XY: 1 AN XY: 362089

African (AFR) AF: 0.00 AC: 0 AN: 26388

American (AMR) AF: 0.00 AC: 0 AN: 35140

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19365

East Asian (EAS) AF: 0.0000664 AC: 2 AN: 30111

South Asian (SAS) AF: 0.00 AC: 0 AN: 53826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40441

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4112

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 841145

Other (OTH) AF: 0.00 AC: 0 AN: 46021

GnomAD4 genome Cov.: 22

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	5.9
DANN	Benign	0.17
DEOGEN2	Benign	0.11	T
FATHMM_MKL	Benign	0.52	D
LIST_S2	Benign	0.65	T
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.076	T
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	0.97	L
PhyloP100		0.48
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.030	N
REVEL	Benign	0.21
Sift	Benign	0.77	T
Sift4G	Benign	0.94	T
Polyphen		0.0	B
Vest4		0.061
MutPred		0.24		Gain of ubiquitination at N635 (P = 7e-04)
MVP		0.75
MPC		0.30
ClinPred		0.015	T
GERP RS		1.4
Varity_R		0.065
gMVP		0.15
Mutation Taster		=96/4	polymorphism

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

Other links and lift over

dbSNP: rs772394005; hg19: chrX-85119692;