rs1923579639

Variant names:

• chrX-85864728-G-A
• rs1923579639
• NM_000390.4:c.1864C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PVS1_Moderate BS2

The NM_000390.4(CHM):​c.1864C>T​(p.Gln622*) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000249 in 1,205,811 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. Q622Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000090 (0 hom., 0 hem., cov: 23)
  • Exomes 𝑓: 0.0000018 (0 hom. 2 hem.)
• Consequence: CHM NM_000390.4 stop_gained
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.93
• 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.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0499 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• BS2: High Hemizygotes in GnomAdExome4 at 2 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.1864C>T	p.Gln622*	stop_gained	Exon 15 of 15	NP_000381.1	P24386-1
	CHM	NM_001320959.1		c.1420C>T	p.Gln474*	stop_gained	Exon 15 of 15	NP_001307888.1	B4DRL9
	CHM	NM_001362517.1		c.1420C>T	p.Gln474*	stop_gained	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.1864C>T	p.Gln622*	stop_gained	Exon 15 of 15	ENSP00000350386.2	P24386-1
	CHM	ENST00000891168.1		c.1861C>T	p.Gln621*	stop_gained	Exon 15 of 15	ENSP00000561227.1
	CHM	ENST00000891170.1		c.1849C>T	p.Gln617*	stop_gained	Exon 15 of 15	ENSP00000561229.1

Frequencies

GnomAD3 genomes AF: 0.00000895 AC: 1 AN: 111697 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

GnomAD4 exome AF: 0.00000183 AC: 2 AN: 1094114 Hom.: 0 Cov.: 29 AF XY: 0.00000556 AC XY: 2 AN XY: 359750

African (AFR) AF: 0.00 AC: 0 AN: 26327

American (AMR) AF: 0.00 AC: 0 AN: 35078

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19340

East Asian (EAS) AF: 0.00 AC: 0 AN: 30081

South Asian (SAS) AF: 0.0000186 AC: 1 AN: 53620

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40398

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4114

European-Non Finnish (NFE) AF: 0.00000119 AC: 1 AN: 839224

Other (OTH) AF: 0.00 AC: 0 AN: 45932

GnomAD4 genome AF: 0.00000895 AC: 1 AN: 111697 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 33867

African (AFR) AF: 0.00 AC: 0 AN: 30715

American (AMR) AF: 0.00 AC: 0 AN: 10490

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2643

East Asian (EAS) AF: 0.00 AC: 0 AN: 3539

South Asian (SAS) AF: 0.00 AC: 0 AN: 2648

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6033

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 236

European-Non Finnish (NFE) AF: 0.0000188 AC: 1 AN: 53205

Other (OTH) AF: 0.00 AC: 0 AN: 1505

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.53
CADD	Pathogenic	33
DANN	Uncertain	0.99
FATHMM_MKL	Uncertain	0.94	D
PhyloP100		3.9
Vest4		0.60
GERP RS		4.9
Mutation Taster		=26/174	disease causing

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: rs1923579639; hg19: chrX-85119733;