NM_000390.4:c.1609+2dupT

Variant names:

• chrX-85878962-T-TA
• rs386833676
• NM_000390.4:c.1609+2dupT

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PVS1_Moderate PM2 PP5

The NM_000390.4(CHM):​c.1609+2dupT variant causes a splice donor, intron change. The variant allele was found at a frequency of 0.00000197 in 1,017,316 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000020 (0 hom. 0 hem.)
• Consequence: CHM NM_000390.4 splice_donor, intron
• Clinical Significance: Pathogenic no assertion criteria provided P:2 O:1
• Conservation: PhyloP100: 5.77
• Publications: 2 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: Uncertain_significance. The variant received 5 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.050458714 fraction of the gene. Cryptic splice site detected, with MaxEntScore 9, offset of 35, new splice context is: aagGTaatg. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-85878962-T-TA is Pathogenic according to our data. Variant chrX-85878962-T-TA is described in ClinVar as [Pathogenic]. Clinvar id is 56224.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHM	NM_000390.4	c.1609+2dupT		splice_donor_variant, intron_variant	Intron 13 of 14	ENST00000357749.7	NP_000381.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHM	ENST00000357749.7	c.1609+2_1609+3insT		splice_donor_variant, intron_variant	Intron 13 of 14	1	NM_000390.4	ENSP00000350386.2
CHM	ENST00000467744.2	n.127-15869_127-15868insT		intron_variant	Intron 2 of 2	5

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD2 exomes AF: 0.0000117 AC: 2 AN: 170427 AF XY: 0.0000173

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000129

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000197 AC: 2 AN: 1017316 Hom.: 0 Cov.: 20 AF XY: 0.00 AC XY: 0 AN XY: 304624

⚠️ 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: 24987

American (AMR) AF: 0.00 AC: 0 AN: 34723

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18690

East Asian (EAS) AF: 0.00 AC: 0 AN: 29672

South Asian (SAS) AF: 0.00 AC: 0 AN: 51596

European-Finnish (FIN) AF: 0.0000498 AC: 2 AN: 40127

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3303

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 770860

Other (OTH) AF: 0.00 AC: 0 AN: 43358

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.029673), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Choroideremia Pathogenic:1 Other:1

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Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

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GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

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Choroideremia, Salla type Pathogenic:1

Jul 01, 1994

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		5.8
Mutation Taster		=1/99	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.93		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.93		Position offset: 3

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs386833676; hg19: chrX-85133967;