chrX-85864735-G-C

Variant names:

• chrX-85864735-G-C
• rs775683467
• NM_000390.4:c.1857C>G

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_000390.4(CHM):​c.1857C>G​(p.Asp619Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000549 in 1,093,590 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. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000055 (0 hom. 3 hem.)
• Consequence: CHM NM_000390.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.388
• 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.10496023).
• BS2: High Hemizygotes in GnomAdExome4 at 3 XL gene

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.1857C>G	p.Asp619Glu	missense	Exon 15 of 15	NP_000381.1	P24386-1
	CHM	NM_001320959.1		c.1413C>G	p.Asp471Glu	missense	Exon 15 of 15	NP_001307888.1	B4DRL9
	CHM	NM_001362517.1		c.1413C>G	p.Asp471Glu	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.1857C>G	p.Asp619Glu	missense	Exon 15 of 15	ENSP00000350386.2	P24386-1
	CHM	ENST00000891168.1		c.1854C>G	p.Asp618Glu	missense	Exon 15 of 15	ENSP00000561227.1
	CHM	ENST00000891170.1		c.1842C>G	p.Asp614Glu	missense	Exon 15 of 15	ENSP00000561229.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD2 exomes AF: 0.0000113 AC: 2 AN: 176796 AF XY: 0.0000323

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000549 AC: 6 AN: 1093590 Hom.: 0 Cov.: 29 AF XY: 0.00000835 AC XY: 3 AN XY: 359214

African (AFR) AF: 0.00 AC: 0 AN: 26326

American (AMR) AF: 0.00 AC: 0 AN: 35085

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19332

East Asian (EAS) AF: 0.0000332 AC: 1 AN: 30087

South Asian (SAS) AF: 0.0000747 AC: 4 AN: 53578

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40405

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4118

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 838747

Other (OTH) AF: 0.0000218 AC: 1 AN: 45912

GnomAD4 genome Cov.: 23

ExAC AF: 0.0000165 AC: 2

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	0.81
DANN	Benign	0.91
DEOGEN2	Benign	0.22	T
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.61	T
M_CAP	Benign	0.035	D
MetaRNN	Benign	0.10	T
MetaSVM	Benign	-0.50	T
MutationAssessor	Benign	2.0	M
PhyloP100		0.39
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.71	N
REVEL	Benign	0.28
Sift	Benign	0.37	T
Sift4G	Benign	0.56	T
Polyphen		0.69	P
Vest4		0.018
MutPred		0.27		Loss of glycosylation at S620 (P = 0.1284)
MVP		0.89
MPC		0.18
ClinPred		0.099	T
GERP RS		-1.2
Varity_R		0.060
gMVP		0.15
Mutation Taster		=100/0	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: rs775683467; hg19: chrX-85119740; COSMIC: COSV63303375;