rs719988

Variant names:

• chrX-85893361-G-A
• rs719988
• NM_000390.4:c.1510+827C>T

Variant summary

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

The NM_000390.4(CHM):​c.1510+827C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.272 in 110,766 control chromosomes in the GnomAD database, including 3,333 homozygotes. There are 8,591 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 0.27 (3333 hom., 8591 hem., cov: 22)
• Consequence: CHM NM_000390.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0920
• Publications: 3 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=-0.93).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.374 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHM	NM_000390.4	c.1510+827C>T		intron_variant	Intron 12 of 14	ENST00000357749.7	NP_000381.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHM	ENST00000357749.7	c.1510+827C>T		intron_variant	Intron 12 of 14	1	NM_000390.4	ENSP00000350386.2
CHM	ENST00000467744.2	n.127-30267C>T		intron_variant	Intron 2 of 2	5

Frequencies

GnomAD3 genomes AF: 0.272 AC: 30169 AN: 110719 Hom.: 3334 Cov.: 22

Gnomad AFR AF: 0.188

Gnomad AMI AF: 0.250

Gnomad AMR AF: 0.383

Gnomad ASJ AF: 0.318

Gnomad EAS AF: 0.00421

Gnomad SAS AF: 0.128

Gnomad FIN AF: 0.313

Gnomad MID AF: 0.270

Gnomad NFE AF: 0.318

Gnomad OTH AF: 0.292

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

GnomAD4 genome AF: 0.272 AC: 30170 AN: 110766 Hom.: 3333 Cov.: 22 AF XY: 0.260 AC XY: 8591 AN XY: 33048

African (AFR) AF: 0.188 AC: 5743 AN: 30546

American (AMR) AF: 0.383 AC: 3990 AN: 10406

Ashkenazi Jewish (ASJ) AF: 0.318 AC: 838 AN: 2636

East Asian (EAS) AF: 0.00423 AC: 15 AN: 3550

South Asian (SAS) AF: 0.127 AC: 337 AN: 2661

European-Finnish (FIN) AF: 0.313 AC: 1822 AN: 5813

Middle Eastern (MID) AF: 0.266 AC: 57 AN: 214

European-Non Finnish (NFE) AF: 0.318 AC: 16762 AN: 52749

Other (OTH) AF: 0.288 AC: 438 AN: 1520

Alfa AF: 0.309 Hom.: 7276

Bravo AF: 0.279

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	1.7
DANN	Benign	0.34
PhyloP100		-0.092
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: rs719988; hg19: chrX-85148366;