X-85864530-G-A

Variant names:

• chrX-85864530-G-A
• NM_000390.4:c.*100C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_000390.4(CHM):​c.*100C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000317 in 631,812 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 0.0000032 (0 hom. 0 hem.)
• Consequence: CHM NM_000390.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.15
• 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: ClinGen, Labcorp Genetics (formerly Invitae), Illumina, Orphanet, G2P

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).

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.*100C>T		3_prime_UTR	Exon 15 of 15	NP_000381.1	P24386-1
	CHM	NM_001320959.1		c.*100C>T		3_prime_UTR	Exon 15 of 15	NP_001307888.1	B4DRL9
	CHM	NM_001362517.1		c.*100C>T		3_prime_UTR	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.*100C>T		3_prime_UTR	Exon 15 of 15	ENSP00000350386.2	P24386-1
	CHM	ENST00000891168.1		c.*100C>T		3_prime_UTR	Exon 15 of 15	ENSP00000561227.1
	CHM	ENST00000891170.1		c.*100C>T		3_prime_UTR	Exon 15 of 15	ENSP00000561229.1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome AF: 0.00000317 AC: 2 AN: 631812 Hom.: 0 Cov.: 10 AF XY: 0.00 AC XY: 0 AN XY: 181950

African (AFR) AF: 0.00 AC: 0 AN: 16766

American (AMR) AF: 0.00 AC: 0 AN: 27396

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15977

East Asian (EAS) AF: 0.00 AC: 0 AN: 25440

South Asian (SAS) AF: 0.00 AC: 0 AN: 41007

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 36844

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2119

European-Non Finnish (NFE) AF: 0.00000229 AC: 1 AN: 435984

Other (OTH) AF: 0.0000330 AC: 1 AN: 30279

GnomAD4 genome Cov.: 24

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	2.0
DANN	Benign	0.23
PhyloP100		1.2

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chrX-85119535;