rs397514603

Variant names:

• chrX-85879054-T-C
• rs397514603
• NM_000390.4:c.1520A>G

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PS3 PM2 PP3_Strong PP5_Moderate

The NM_000390.4(CHM):​c.1520A>G​(p.His507Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000000937 in 1,067,739 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). ClinVar reports functional evidence for this variant: "SCV005904772: Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID:21905166).". Synonymous variant affecting the same amino acid position (i.e. H507H) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 9.4e-7 (0 hom. 1 hem.)
• Consequence: CHM NM_000390.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:3
• Conservation: PhyloP100: 5.00
• Publications: 12 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: Pathogenic. The variant received 12 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV005904772: Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 21905166).
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.957
• PP5: Variant X-85879054-T-C is Pathogenic according to our data. Variant chrX-85879054-T-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 39809.Status of the report is criteria_provided_single_submitter, 1 stars.

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.1520A>G	p.His507Arg	missense	Exon 13 of 15	NP_000381.1	P24386-1
	CHM	NM_001320959.1		c.1076A>G	p.His359Arg	missense	Exon 13 of 15	NP_001307888.1	B4DRL9
	CHM	NM_001362517.1		c.1076A>G	p.His359Arg	missense	Exon 13 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.1520A>G	p.His507Arg	missense	Exon 13 of 15	ENSP00000350386.2	P24386-1
	CHM	ENST00000891168.1		c.1517A>G	p.His506Arg	missense	Exon 13 of 15	ENSP00000561227.1
	CHM	ENST00000891170.1		c.1520A>G	p.His507Arg	missense	Exon 13 of 15	ENSP00000561229.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 9.37e-7 AC: 1 AN: 1067739 Hom.: 0 Cov.: 26 AF XY: 0.00000298 AC XY: 1 AN XY: 336059

African (AFR) AF: 0.00 AC: 0 AN: 25900

American (AMR) AF: 0.00 AC: 0 AN: 34710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18971

East Asian (EAS) AF: 0.00 AC: 0 AN: 29904

South Asian (SAS) AF: 0.00 AC: 0 AN: 52472

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40006

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3868

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 816913

Other (OTH) AF: 0.0000222 AC: 1 AN: 44995

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
3	-	-	Choroideremia (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.54
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.97	D
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.95	D
M_CAP	Uncertain	0.19	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Uncertain	0.41	D
MutationAssessor	Pathogenic	3.6	H
PhyloP100		5.0
PrimateAI	Uncertain	0.63	T
PROVEAN	Pathogenic	-7.0	D
REVEL	Pathogenic	0.75
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.95
MutPred		0.78		Gain of MoRF binding (P = 0.0184)
MVP		1.0
MPC		0.85
ClinPred		1.0	D
GERP RS		2.8
Varity_R		0.98
gMVP		0.93
Mutation Taster		=3/97	disease causing (ClinVar)

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: rs397514603; hg19: chrX-85134059;