rs863225075

Positions:

• chr13-114325386-G-A
• chr13-114325386-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_032436.4(CHAMP1):​c.1544G>A​(p.Trp515*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CHAMP1 NM_032436.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 1.48

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 Likely_pathogenic. Variant got 8 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. Fraction of 0.367 CDS is truncated, and there are 3 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 13-114325386-G-A is Pathogenic according to our data. Variant chr13-114325386-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 217907.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHAMP1	NM_032436.4	c.1544G>A	p.Trp515*	stop_gained	3/3	ENST00000361283.4	NP_115812.1
CHAMP1	NM_001164144.3	c.1544G>A	p.Trp515*	stop_gained	3/3		NP_001157616.1
CHAMP1	NM_001164145.3	c.1544G>A	p.Trp515*	stop_gained	3/3		NP_001157617.1
CHAMP1	XM_047430277.1	c.1544G>A	p.Trp515*	stop_gained	3/3		XP_047286233.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHAMP1	ENST00000361283.4	c.1544G>A	p.Trp515*	stop_gained	3/3	1	NM_032436.4	ENSP00000354730.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Oct 16, 2015

The W515X pathogenic variant in the CHAMP1 gene has not been reported previously as apathogenic variant nor as a benign variant, to our knowledge. This variant is predicted to cause loss ofnormal protein function through protein truncation. The W515X variant was not observed inapproximately 6,500 individuals of European and African American ancestry in the NHLBI ExomeSequencing Project, indicating it is not a common benign variant in these populations. We interpretW515X as a pathogenic variant. -

CHAMP1-related syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

provider interpretation

GenomeConnect - Simons Searchlight

Mar 18, 2019

Submission from Simons Searchlight facilitated by GenomeConnect. Variant interpreted by the Simons Searchlight team most recently on 2019-03-18 and interpreted as Pathogenic. Variant was initially reported on 2015-12-02 by GTR ID of laboratory name 26957. The reporting laboratory might also submit to ClinVar. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.62
CADD	Pathogenic	38
DANN	Uncertain	1.0
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Benign	0.64	D
Vest4		0.13
GERP RS		5.8

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: rs863225075; hg19: chr13-115090861;