15-40605819-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_144508.5(KNL1):c.76-574C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0837 in 152,216 control chromosomes in the GnomAD database, including 546 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.084 (546 hom., cov: 32)
• Consequence: KNL1 NM_144508.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.886

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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.112 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KNL1	NM_144508.5	c.76-574C>T		intron_variant		ENST00000399668.7
KNL1	NM_170589.5	c.76-574C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KNL1	ENST00000399668.7	c.76-574C>T		intron_variant		1	NM_144508.5	A2

Frequencies

GnomAD3 genomes AF: 0.0836 AC: 12721 AN: 152098 Hom.: 541 Cov.: 32

Gnomad AFR AF: 0.115

Gnomad AMI AF: 0.0595

Gnomad AMR AF: 0.0624

Gnomad ASJ AF: 0.0369

Gnomad EAS AF: 0.118

Gnomad SAS AF: 0.111

Gnomad FIN AF: 0.0768

Gnomad MID AF: 0.0854

Gnomad NFE AF: 0.0688

Gnomad OTH AF: 0.0770

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0837 AC: 12735 AN: 152216 Hom.: 546 Cov.: 32 AF XY: 0.0838 AC XY: 6238 AN XY: 74434

Gnomad4 AFR AF: 0.115

Gnomad4 AMR AF: 0.0625

Gnomad4 ASJ AF: 0.0369

Gnomad4 EAS AF: 0.117

Gnomad4 SAS AF: 0.111

Gnomad4 FIN AF: 0.0768

Gnomad4 NFE AF: 0.0688

Gnomad4 OTH AF: 0.0771

Alfa AF: 0.0653 Hom.: 526

Bravo AF: 0.0843

Asia WGS AF: 0.102 AC: 353 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
Cadd	Benign	0.45
Dann	Benign	0.73

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: rs10518696; hg19: chr15-40898017;