NM_000390.4:c.1584_1587delTGTT

Variant names:

• chrX-85878986-GAACA-G
• rs587776746
• NM_000390.4:c.1584_1587delTGTT

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000390.4(CHM):​c.1584_1587delTGTT​(p.Val529HisfsTer7) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000168 in 1,193,911 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.0000090 (0 hom., 0 hem., cov: 22)
  • Exomes 𝑓: 9.2e-7 (0 hom. 0 hem.)
• Consequence: CHM NM_000390.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6 O:1
• Conservation: PhyloP100: 1.62
• Publications: 11 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: Pathogenic. The variant received 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-85878986-GAACA-G is Pathogenic according to our data. Variant chrX-85878986-GAACA-G is described in ClinVar as Pathogenic. ClinVar VariationId is 11152.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHM	NM_000390.4	MANE Select	c.1584_1587delTGTT	p.Val529HisfsTer7	frameshift	Exon 13 of 15	NP_000381.1
	CHM	NM_001320959.1		c.1140_1143delTGTT	p.Val381HisfsTer7	frameshift	Exon 13 of 15	NP_001307888.1
	CHM	NM_001362517.1		c.1140_1143delTGTT	p.Val381HisfsTer7	frameshift	Exon 13 of 15	NP_001349446.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHM	ENST00000357749.7	TSL:1 MANE Select	c.1584_1587delTGTT	p.Val529HisfsTer7	frameshift	Exon 13 of 15	ENSP00000350386.2
	CHM	ENST00000891168.1		c.1581_1584delTGTT	p.Val528HisfsTer7	frameshift	Exon 13 of 15	ENSP00000561227.1
	CHM	ENST00000891170.1		c.1584_1587delTGTT	p.Val529HisfsTer7	frameshift	Exon 13 of 15	ENSP00000561229.1

Frequencies

GnomAD3 genomes AF: 0.00000899 AC: 1 AN: 111237 Hom.: 0 Cov.: 22

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: 0.0000189

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 9.24e-7 AC: 1 AN: 1082674 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 350314

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 26136

American (AMR) AF: 0.00 AC: 0 AN: 34986

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19153

East Asian (EAS) AF: 0.00 AC: 0 AN: 29956

South Asian (SAS) AF: 0.00 AC: 0 AN: 53283

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40292

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3738

European-Non Finnish (NFE) AF: 0.00000121 AC: 1 AN: 829613

Other (OTH) AF: 0.00 AC: 0 AN: 45517

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00000899 AC: 1 AN: 111237 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 33513

African (AFR) AF: 0.00 AC: 0 AN: 30581

American (AMR) AF: 0.00 AC: 0 AN: 10403

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2640

East Asian (EAS) AF: 0.00 AC: 0 AN: 3566

South Asian (SAS) AF: 0.00 AC: 0 AN: 2677

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5948

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

European-Non Finnish (NFE) AF: 0.0000189 AC: 1 AN: 53011

Other (OTH) AF: 0.00 AC: 0 AN: 1491

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	Choroideremia (4)
2	-	-	not provided (2)
1	-	-	Retinal dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.6
Mutation Taster		=4/196	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: rs587776746; hg19: chrX-85133991;