X-85932135-G-T

Variant names:

• chrX-85932135-G-T
• rs11092732
• NM_000390.4:c.1167-20797C>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000390.4(CHM):​c.1167-20797C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.207 in 111,205 control chromosomes in the GnomAD database, including 2,034 homozygotes. There are 6,932 hemizygotes 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: 𝑓 0.21 (2034 hom., 6932 hem., cov: 23)
• Consequence: CHM NM_000390.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.881
• Publications: 1 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: Labcorp Genetics (formerly Invitae), Orphanet, G2P, ClinGen, Illumina

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.506 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHM	NM_000390.4	c.1167-20797C>A		intron_variant	Intron 8 of 14	ENST00000357749.7	NP_000381.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHM	ENST00000357749.7	c.1167-20797C>A		intron_variant	Intron 8 of 14	1	NM_000390.4	ENSP00000350386.2
CHM	ENST00000467744.2	n.127-69041C>A		intron_variant	Intron 2 of 2	5

Frequencies

GnomAD3 genomes AF: 0.207 AC: 23060 AN: 111156 Hom.: 2035 Cov.: 23

Gnomad AFR AF: 0.0907

Gnomad AMI AF: 0.176

Gnomad AMR AF: 0.239

Gnomad ASJ AF: 0.211

Gnomad EAS AF: 0.527

Gnomad SAS AF: 0.348

Gnomad FIN AF: 0.251

Gnomad MID AF: 0.296

Gnomad NFE AF: 0.236

Gnomad OTH AF: 0.197

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.207 AC: 23053 AN: 111205 Hom.: 2034 Cov.: 23 AF XY: 0.207 AC XY: 6932 AN XY: 33431

African (AFR) AF: 0.0905 AC: 2781 AN: 30738

American (AMR) AF: 0.239 AC: 2495 AN: 10437

Ashkenazi Jewish (ASJ) AF: 0.211 AC: 555 AN: 2636

East Asian (EAS) AF: 0.526 AC: 1822 AN: 3463

South Asian (SAS) AF: 0.351 AC: 916 AN: 2609

European-Finnish (FIN) AF: 0.251 AC: 1488 AN: 5921

Middle Eastern (MID) AF: 0.302 AC: 64 AN: 212

European-Non Finnish (NFE) AF: 0.236 AC: 12514 AN: 52997

Other (OTH) AF: 0.197 AC: 298 AN: 1511

Alfa AF: 0.232 Hom.: 13426

Bravo AF: 0.205

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.81
DANN	Benign	0.55
PhyloP100		0.88
Mutation Taster		=100/0	polymorphism (auto)

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: rs11092732; hg19: chrX-85187140;