15-40606590-G-A

Position:

• chr15-40606590-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_144508.5(KNL1):​c.135+138G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0501 in 531,594 control chromosomes in the GnomAD database, including 842 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.042 (168 hom., cov: 32)
  • Exomes 𝑓: 0.053 (674 hom.)
• Consequence: KNL1 NM_144508.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.108

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]

KNL1 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 15-40606590-G-A is Benign according to our data. Variant chr15-40606590-G-A is described in ClinVar as [Benign]. Clinvar id is 1256682.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.11 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KNL1	NM_144508.5	c.135+138G>A		intron_variant		ENST00000399668.7	NP_653091.3
KNL1	NM_170589.5	c.135+138G>A		intron_variant			NP_733468.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KNL1	ENST00000399668.7	c.135+138G>A		intron_variant		1	NM_144508.5	ENSP00000382576.3

Frequencies

GnomAD3 genomes AF: 0.0421 AC: 6399 AN: 152096 Hom.: 166 Cov.: 32

Gnomad AFR AF: 0.00857

Gnomad AMI AF: 0.0407

Gnomad AMR AF: 0.0405

Gnomad ASJ AF: 0.0187

Gnomad EAS AF: 0.118

Gnomad SAS AF: 0.107

Gnomad FIN AF: 0.0591

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0511

Gnomad OTH AF: 0.0398

GnomAD4 exome AF: 0.0533 AC: 20208 AN: 379380 Hom.: 674 AF XY: 0.0550 AC XY: 10879 AN XY: 197974

Gnomad4 AFR exome AF: 0.00830

Gnomad4 AMR exome AF: 0.0433

Gnomad4 ASJ exome AF: 0.0169

Gnomad4 EAS exome AF: 0.0905

Gnomad4 SAS exome AF: 0.0904

Gnomad4 FIN exome AF: 0.0583

Gnomad4 NFE exome AF: 0.0485

Gnomad4 OTH exome AF: 0.0487

GnomAD4 genome AF: 0.0421 AC: 6401 AN: 152214 Hom.: 168 Cov.: 32 AF XY: 0.0439 AC XY: 3265 AN XY: 74426

Gnomad4 AFR AF: 0.00855

Gnomad4 AMR AF: 0.0408

Gnomad4 ASJ AF: 0.0187

Gnomad4 EAS AF: 0.118

Gnomad4 SAS AF: 0.107

Gnomad4 FIN AF: 0.0591

Gnomad4 NFE AF: 0.0511

Gnomad4 OTH AF: 0.0403

Alfa AF: 0.0501 Hom.: 44

Bravo AF: 0.0390

Asia WGS AF: 0.0910 AC: 315 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 26, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.56
DANN	Benign	0.19

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs74363042; hg19: chr15-40898788;