rs863225076

chr13-114324884-TG-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_032436.4(CHAMP1):c.1044del(p.Trp348Ter) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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:1
• Conservation: PhyloP100: 2.75

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 12 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 29 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 13-114324884-TG-T is Pathogenic according to our data. Variant chr13-114324884-TG-T is described in ClinVar as [Pathogenic]. Clinvar id is 217908.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.1044del	p.Trp348Ter	frameshift_variant	3/3	ENST00000361283.4
CHAMP1	NM_001164144.3	c.1044del	p.Trp348Ter	frameshift_variant	3/3
CHAMP1	NM_001164145.3	c.1044del	p.Trp348Ter	frameshift_variant	3/3
CHAMP1	XM_047430277.1	c.1044del	p.Trp348Ter	frameshift_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHAMP1	ENST00000361283.4	c.1044del	p.Trp348Ter	frameshift_variant	3/3	1	NM_032436.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Oct 16, 2015

c.1044delG: p.Trp348Ter in exon 3 in the CHAMP1 gene (NM_001164144.1). The normal sequence with the base that is deleted in braces is: CTTG{G}AAAC. The c.1044delG pathogenic variant in the CHAMP1 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The c.1044delG variant changes codon Tryptophan 348 to a premature Stop codon, denoted p.Trp348Ter. This variant is predicted to cause loss of normal protein function through protein truncation. Protein truncating variants downstream of this variant have been reported in association with intellectual disability (Hempel et al., 2015), supporting the pathogenicity of more upstream truncating variants. The c.1044delG variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. We interpret c.1044delG as a pathogenic variant. This variant has been observed de novo with confirmed parentage. -

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: rs863225076; hg19: chr13-115090359;