rs3092978

Variant names:

• chr15-40634781-A-G
• rs3092978
• NM_144508.5:c.5682+5410A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_144508.5(KNL1):​c.5682+5410A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.785 in 152,046 control chromosomes in the GnomAD database, including 47,826 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 0.78 (47826 hom., cov: 30)
• Consequence: KNL1 NM_144508.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0340
• Publications: 3 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: Labcorp Genetics (formerly Invitae), Ambry Genetics
• autosomal recessive primary microcephaly

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.01).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.845 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_144508.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KNL1	NM_144508.5	MANE Select	c.5682+5410A>G		intron	N/A	NP_653091.3	Q8NG31-2
	KNL1	NM_170589.5		c.5760+5410A>G		intron	N/A	NP_733468.3	Q8NG31-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KNL1	ENST00000399668.7	TSL:1 MANE Select	c.5682+5410A>G		intron	N/A	ENSP00000382576.3	Q8NG31-2
	KNL1	ENST00000346991.9	TSL:1	c.5760+5410A>G		intron	N/A	ENSP00000335463.6	Q8NG31-1
	KNL1	ENST00000526913.5	TSL:1	n.2814+5410A>G		intron	N/A	ENSP00000432565.1	H0YCZ2

Frequencies

GnomAD3 genomes AF: 0.785 AC: 119254 AN: 151928 Hom.: 47788 Cov.: 30

Gnomad AFR AF: 0.769

Gnomad AMI AF: 0.763

Gnomad AMR AF: 0.660

Gnomad ASJ AF: 0.807

Gnomad EAS AF: 0.323

Gnomad SAS AF: 0.727

Gnomad FIN AF: 0.847

Gnomad MID AF: 0.847

Gnomad NFE AF: 0.851

Gnomad OTH AF: 0.776

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

GnomAD4 genome AF: 0.785 AC: 119335 AN: 152046 Hom.: 47826 Cov.: 30 AF XY: 0.780 AC XY: 57959 AN XY: 74328

African (AFR) AF: 0.769 AC: 31882 AN: 41434

American (AMR) AF: 0.660 AC: 10063 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.807 AC: 2797 AN: 3468

East Asian (EAS) AF: 0.323 AC: 1666 AN: 5164

South Asian (SAS) AF: 0.727 AC: 3503 AN: 4820

European-Finnish (FIN) AF: 0.847 AC: 8976 AN: 10602

Middle Eastern (MID) AF: 0.836 AC: 244 AN: 292

European-Non Finnish (NFE) AF: 0.851 AC: 57874 AN: 67992

Other (OTH) AF: 0.776 AC: 1634 AN: 2106

Alfa AF: 0.823 Hom.: 7849

Bravo AF: 0.761

Asia WGS AF: 0.549 AC: 1911 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	1.4
DANN	Benign	0.62
PhyloP100		0.034
Mutation Taster		=99/1	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: rs3092978; hg19: chr15-40926979;