chrX-85864752-T-C

Variant names:

• chrX-85864752-T-C
• rs760324593
• NM_000390.4:c.1840A>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_000390.4(CHM):​c.1840A>G​(p.Ile614Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000116 in 1,206,815 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000089 (0 hom., 0 hem., cov: 23)
  • Exomes 𝑓: 0.000012 (0 hom. 1 hem.)
• Consequence: CHM NM_000390.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.28
• 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 -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.16291252).

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.1840A>G	p.Ile614Val	missense	Exon 15 of 15	NP_000381.1	P24386-1
	CHM	NM_001320959.1		c.1396A>G	p.Ile466Val	missense	Exon 15 of 15	NP_001307888.1	B4DRL9
	CHM	NM_001362517.1		c.1396A>G	p.Ile466Val	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.1840A>G	p.Ile614Val	missense	Exon 15 of 15	ENSP00000350386.2	P24386-1
	CHM	ENST00000891168.1		c.1837A>G	p.Ile613Val	missense	Exon 15 of 15	ENSP00000561227.1
	CHM	ENST00000891170.1		c.1825A>G	p.Ile609Val	missense	Exon 15 of 15	ENSP00000561229.1

Frequencies

GnomAD3 genomes AF: 0.00000894 AC: 1 AN: 111895 Hom.: 0 Cov.: 23

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

GnomAD2 exomes AF: 0.0000113 AC: 2 AN: 176434 AF XY: 0.00

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: 0.0000257

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000119 AC: 13 AN: 1094920 Hom.: 0 Cov.: 29 AF XY: 0.00000277 AC XY: 1 AN XY: 360534

African (AFR) AF: 0.00 AC: 0 AN: 26346

American (AMR) AF: 0.00 AC: 0 AN: 35092

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19334

East Asian (EAS) AF: 0.00 AC: 0 AN: 30086

South Asian (SAS) AF: 0.00 AC: 0 AN: 53514

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40403

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4125

European-Non Finnish (NFE) AF: 0.0000119 AC: 10 AN: 840044

Other (OTH) AF: 0.0000653 AC: 3 AN: 45976

GnomAD4 genome AF: 0.00000894 AC: 1 AN: 111895 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 34071

African (AFR) AF: 0.00 AC: 0 AN: 30762

American (AMR) AF: 0.00 AC: 0 AN: 10496

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2655

East Asian (EAS) AF: 0.00 AC: 0 AN: 3552

South Asian (SAS) AF: 0.00 AC: 0 AN: 2664

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6093

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 237

European-Non Finnish (NFE) AF: 0.0000188 AC: 1 AN: 53243

Other (OTH) AF: 0.00 AC: 0 AN: 1509

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000165 AC: 2

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	0.12
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Benign	0.31	T
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-0.81	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		2.3
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.84	N
REVEL	Benign	0.12
Sift	Benign	0.039	D
Sift4G	Benign	0.14	T
Polyphen		0.010	B
Vest4		0.12
MutPred		0.33		Gain of sheet (P = 0.1208)
MVP		0.69
MPC		0.16
ClinPred		0.45	T
GERP RS		4.9
Varity_R		0.46
gMVP		0.31
Mutation Taster		=90/10	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: rs760324593; hg19: chrX-85119757;