13-114324359-TCTC-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 3P and 12B. PM1 PM4_Supporting BP6_Very_Strong BS2

The NM_032436.4(CHAMP1):c.520_522del(p.Pro174del) variant causes a inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00209 in 1,614,006 control chromosomes in the GnomAD database, including 7 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0022 (7 hom.)
• Consequence: CHAMP1 NM_032436.4 inframe_deletion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 3.01

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 Benign. Variant got -9 ACMG points.

• PM1: In a modified_residue Phosphoserine (size 0) in uniprot entity CHAP1_HUMAN
• PM4: Nonframeshift variant in NON repetitive region in NM_032436.4. Strenght limited to Supporting due to length of the change: 1aa.
• BP6: Variant 13-114324359-TCTC-T is Benign according to our data. Variant chr13-114324359-TCTC-T is described in ClinVar as [Likely_benign]. Clinvar id is 731051.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd at 199 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHAMP1	NM_032436.4	c.520_522del	p.Pro174del	inframe_deletion	3/3	ENST00000361283.4
CHAMP1	NM_001164144.3	c.520_522del	p.Pro174del	inframe_deletion	3/3
CHAMP1	NM_001164145.3	c.520_522del	p.Pro174del	inframe_deletion	3/3
CHAMP1	XM_047430277.1	c.520_522del	p.Pro174del	inframe_deletion	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHAMP1	ENST00000361283.4	c.520_522del	p.Pro174del	inframe_deletion	3/3	1	NM_032436.4	P1

Frequencies

GnomAD3 genomes AF: 0.00131 AC: 199 AN: 152002 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000338

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000472

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00250

Gnomad OTH AF: 0.000480

GnomAD3 exomes AF: 0.00142 AC: 358 AN: 251468 Hom.: 1 AF XY: 0.00138 AC XY: 187 AN XY: 135904

Gnomad AFR exome AF: 0.000554

Gnomad AMR exome AF: 0.000694

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000647

Gnomad NFE exome AF: 0.00258

Gnomad OTH exome AF: 0.00277

GnomAD4 exome AF: 0.00217 AC: 3168 AN: 1461886 Hom.: 7 AF XY: 0.00216 AC XY: 1571 AN XY: 727244

Gnomad4 AFR exome AF: 0.000418

Gnomad4 AMR exome AF: 0.000671

Gnomad4 ASJ exome AF: 0.000191

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00116

Gnomad4 NFE exome AF: 0.00263

Gnomad4 OTH exome AF: 0.00222

GnomAD4 genome AF: 0.00131 AC: 199 AN: 152120 Hom.: 0 Cov.: 32 AF XY: 0.00114 AC XY: 85 AN XY: 74368

Gnomad4 AFR AF: 0.000337

Gnomad4 AMR AF: 0.000589

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000472

Gnomad4 NFE AF: 0.00250

Gnomad4 OTH AF: 0.000475

Alfa AF: 0.000538 Hom.: 0

Bravo AF: 0.00137

EpiCase AF: 0.00202

EpiControl AF: 0.00279

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	CHAMP1: PM4:Supporting, BS1, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Dec 31, 2019	- -

CHAMP1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 24, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

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: rs535593712; hg19: chr13-115089834;