rs3092979

Variant names:

• chr15-40645449-A-G
• rs3092979
• NM_144508.5:c.5890-207A>G

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 10 publications found

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 Gene-Disease associations (from GenCC):

• microcephaly 4, primary, autosomal recessive

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• autosomal recessive primary microcephaly

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000259254 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
KNL1	NM_144508.5	c.5890-207A>G		intron_variant	Intron 15 of 25	ENST00000399668.7	NP_653091.3
KNL1	NM_170589.5	c.5968-207A>G		intron_variant	Intron 16 of 26		NP_733468.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KNL1	ENST00000399668.7	c.5890-207A>G		intron_variant	Intron 15 of 25	1	NM_144508.5	ENSP00000382576.3

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

African (AFR) AF: 0.365 AC: 15131 AN: 41456

American (AMR) AF: 0.327 AC: 4997 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.405 AC: 1405 AN: 3472

East Asian (EAS) AF: 0.246 AC: 1277 AN: 5186

South Asian (SAS) AF: 0.460 AC: 2216 AN: 4816

European-Finnish (FIN) AF: 0.470 AC: 4962 AN: 10550

Middle Eastern (MID) AF: 0.469 AC: 138 AN: 294

European-Non Finnish (NFE) AF: 0.409 AC: 27814 AN: 67986

Other (OTH) AF: 0.373 AC: 786 AN: 2110

Alfa AF: 0.417 Hom.: 1813

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

Jul 17, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	5.0
DANN	Benign	0.73
PhyloP100		0.080
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3092979; hg19: chr15-40937647;