15-40604907-A-G

Position:

• chr15-40604907-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_144508.5(KNL1):​c.36-203A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00845 in 152,312 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency: Genomes: 𝑓 0.0084 (9 hom., cov: 32)
• Consequence: KNL1 NM_144508.5 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.700

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=-0.88).
• BP6: Variant 15-40604907-A-G is Benign according to our data. Variant chr15-40604907-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 1193032.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00845 (1287/152312) while in subpopulation NFE AF= 0.0146 (994/68036). AF 95% confidence interval is 0.0139. There are 9 homozygotes in gnomad4. There are 584 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KNL1	NM_144508.5	c.36-203A>G		intron_variant		ENST00000399668.7	NP_653091.3
KNL1	NM_170589.5	c.36-203A>G		intron_variant			NP_733468.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KNL1	ENST00000399668.7	c.36-203A>G		intron_variant		1	NM_144508.5	ENSP00000382576.3

Frequencies

GnomAD3 genomes AF: 0.00846 AC: 1287 AN: 152194 Hom.: 9 Cov.: 32

Gnomad AFR AF: 0.00193

Gnomad AMI AF: 0.0363

Gnomad AMR AF: 0.00393

Gnomad ASJ AF: 0.0121

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.00480

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0146

Gnomad OTH AF: 0.00574

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

GnomAD4 genome AF: 0.00845 AC: 1287 AN: 152312 Hom.: 9 Cov.: 32 AF XY: 0.00784 AC XY: 584 AN XY: 74482

Gnomad4 AFR AF: 0.00193

Gnomad4 AMR AF: 0.00392

Gnomad4 ASJ AF: 0.0121

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00269

Gnomad4 FIN AF: 0.00480

Gnomad4 NFE AF: 0.0146

Gnomad4 OTH AF: 0.00568

Alfa AF: 0.0150 Hom.: 6

Bravo AF: 0.00764

Asia WGS AF: 0.00116 AC: 4 AN: 3474

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 17, 2018	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	7.0
DANN	Benign	0.61

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: rs118122124; hg19: chr15-40897105;