rs3092979

Positions:

• chr15-40645449-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_144508.5(KNL1):​c.5890-207A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.389 in 152,052 control chromosomes in the GnomAD database, including 11,687 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.39 (11687 hom., cov: 33)
• Consequence: KNL1 NM_144508.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0800

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 15-40645449-A-G is Benign according to our data. Variant chr15-40645449-A-G is described in ClinVar as [Benign]. Clinvar id is 1292995.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.444 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KNL1	NM_144508.5	c.5890-207A>G		intron_variant		ENST00000399668.7
KNL1	NM_170589.5	c.5968-207A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KNL1	ENST00000399668.7	c.5890-207A>G		intron_variant		1	NM_144508.5	A2
	ENST00000559841.1	n.375-1267A>G		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.389 AC: 59032 AN: 151934 Hom.: 11669 Cov.: 33

Gnomad AFR AF: 0.365

Gnomad AMI AF: 0.393

Gnomad AMR AF: 0.327

Gnomad ASJ AF: 0.405

Gnomad EAS AF: 0.246

Gnomad SAS AF: 0.460

Gnomad FIN AF: 0.470

Gnomad MID AF: 0.481

Gnomad NFE AF: 0.409

Gnomad OTH AF: 0.369

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

GnomAD4 genome AF: 0.389 AC: 59084 AN: 152052 Hom.: 11687 Cov.: 33 AF XY: 0.391 AC XY: 29056 AN XY: 74304

Gnomad4 AFR AF: 0.365

Gnomad4 AMR AF: 0.327

Gnomad4 ASJ AF: 0.405

Gnomad4 EAS AF: 0.246

Gnomad4 SAS AF: 0.460

Gnomad4 FIN AF: 0.470

Gnomad4 NFE AF: 0.409

Gnomad4 OTH AF: 0.373

Alfa AF: 0.420 Hom.: 1767

Bravo AF: 0.371

Asia WGS AF: 0.370 AC: 1284 AN: 3472

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 17, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	5.0
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: rs3092979; hg19: chr15-40937647;