rs863225127

chr15-40625447-C-CT

Variant summary

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

The NM_144508.5(KNL1):c.5184dup(p.Ile1729TyrfsTer2) 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 (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: KNL1 NM_144508.5 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: -0.0640

Genes affected

KNL1 (HGNC:24054): (kinetochore scaffold 1) The protein encoded by this gene is a component of the multiprotein assembly that is required for creation of kinetochore-microtubule attachments and chromosome segregation. The encoded protein functions as a scaffold for proteins that influence the spindle assembly checkpoint during the eukaryotic cell cycle and it interacts with at least five different kinetochore proteins and two checkpoint kinases. In adults, this gene is predominantly expressed in normal testes, various cancer cell lines and primary tumors from other tissues and is ubiquitously expressed in fetal tissues. This gene was originally identified as a fusion partner with the mixed-lineage leukemia (MLL) gene in t(11;15)(q23;q14). Mutations in this gene cause autosomal recessive primary microcephaly-4 (MCPH4). Alternative splicing results in multiple transcript variants encoding different isoforms. Additional splice variants have been described but their biological validity has not been confirmed. [provided by RefSeq, Jan 2013]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 15-40625447-C-CT is Pathogenic according to our data. Variant chr15-40625447-C-CT is described in ClinVar as [Pathogenic]. Clinvar id is 217515.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KNL1	NM_144508.5	c.5184dup	p.Ile1729TyrfsTer2	frameshift_variant	10/26	ENST00000399668.7
KNL1	NM_170589.5	c.5262dup	p.Ile1755TyrfsTer2	frameshift_variant	11/27

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KNL1	ENST00000399668.7	c.5184dup	p.Ile1729TyrfsTer2	frameshift_variant	10/26	1	NM_144508.5	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Microcephaly 4, primary, autosomal recessive Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 20, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Molecular Genetics Pathology Laboratory, University Of Arkansas for Medical Sciences	Oct 26, 2015	The c.5262dup change is a previously unreported variant that results in a frameshift (p.Ile1755Tyrfs*2) and premature truncation of the protein encoded by this gene. The c.5262dupT is classified as pathogenic (PVS1 PS2). As a frameshift variant, it falls in the PVS1 category. Because of its de novo nature, it is also a category PS2 variant, fulfilling criteria for pathogenicity. -

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: rs863225127; hg19: chr15-40917645;