rs863225077

chr13-114324381-CCT-C

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PP5_Moderate

The NM_032436.4(CHAMP1):c.542_543del(p.Ser181CysfsTer5) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CHAMP1 NM_032436.4 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:2 O:1
• Conservation: PhyloP100: -0.0500

Genes affected

CHAMP1 (HGNC:20311): (chromosome alignment maintaining phosphoprotein 1) This gene encodes a zinc finger protein that functions as a regulator of chromosome segregation in mitosis. The encoded protein is required for correct alignment of chromosomes on the metaphase plate, and plays a role in maintaining the attachment of sister kinetochores to microtubules from opposite spindle poles. Mutations in this gene are associated with an autosomal dominant form of intellectual disability. [provided by RefSeq, Jul 2017]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 38 pathogenic variants in the truncated region.
• PP5: Variant 13-114324381-CCT-C is Pathogenic according to our data. Variant chr13-114324381-CCT-C is described in ClinVar as [Pathogenic]. Clinvar id is 217909.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHAMP1	NM_032436.4	c.542_543del	p.Ser181CysfsTer5	frameshift_variant	3/3	ENST00000361283.4
CHAMP1	NM_001164144.3	c.542_543del	p.Ser181CysfsTer5	frameshift_variant	3/3
CHAMP1	NM_001164145.3	c.542_543del	p.Ser181CysfsTer5	frameshift_variant	3/3
CHAMP1	XM_047430277.1	c.542_543del	p.Ser181CysfsTer5	frameshift_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHAMP1	ENST00000361283.4	c.542_543del	p.Ser181CysfsTer5	frameshift_variant	3/3	1	NM_032436.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

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

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Mar 14, 2018

The c.542_543delCT variant in the CHAMP1 gene has been reported previously as a de novo variant in an individual with global developmental delay, intellectual disability, dysmorphic features, and spasticity (Tanaka et al., 2016). The c.542_543delCT variant causes a frameshift starting with codon Serine 181, changes this amino acid to a Cysteine residue, and creates a premature Stop codon at position 5 of the new reading frame, denoted p.Ser181CysfsX5. This variant is predicted to cause loss of normal protein function through protein truncation, as the last 632 amino acids are replaced with 4 incorrect amino acids. Furthermore, the c.542_543delCT variant is not observed in large population cohorts (Lek et al., 2016). We interpret c.542_543delCT as a pathogenic variant. -

CHAMP1-related syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

provider interpretation

GenomeConnect - Simons Searchlight

Apr 20, 2018

Submission from Simons Searchlight facilitated by GenomeConnect. Variant interpreted by the Simons Searchlight team most recently on 2018-04-20 and interpreted as Pathogenic. Variant was initially reported on 2018-03-27 by GTR ID of laboratory name 26957. The reporting laboratory might also submit to ClinVar. -

Intellectual disability, autosomal dominant 40 Other:1

not provided, no classification provided

phenotyping only

GenomeConnect - Brain Gene Registry

-

Variant interpreted as Pathogenic and reported on 03-27-2018 by Lab or GTR ID 26957. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect does not attempt to reinterpret the variant. The IDDRC-CTSA National Brain Gene Registry (BGR ) is a study funded by the U.S. National Center for Advancing Translational Sciences (NCATS) and includes 13 Intellectual and Developmental Disability Research Center (IDDRC) institutions. The study is led by Principal Investigator John Constantino MD PhD from Washington University. The BGR is a data commons of gene variants paired with subject clinical information. This database helps scientists learn more about genetic changes and their impact on the brain and behavior. Participation in the Brain Gene Registry requires participation in GenomeConnect. -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs863225077; hg19: chr13-115089856;