rs587780294

Variant names:

• chr15-40647074-GGTAAA-G
• rs587780294
• NM_144508.5:c.6094+4_6094+8delAAGTA

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_144508.5(KNL1):​c.6094+4_6094+8delAAGTA variant causes a splice region, intron change. The variant allele was found at a frequency of 0.000232 in 1,412,864 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00024 (0 hom.)
• Consequence: KNL1 NM_144508.5 splice_region, intron
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.87
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KNL1	NM_144508.5	MANE Select	c.6094+4_6094+8delAAGTA		splice_region intron	N/A	NP_653091.3
	KNL1	NM_170589.5		c.6172+4_6172+8delAAGTA		splice_region intron	N/A	NP_733468.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KNL1	ENST00000399668.7	TSL:1 MANE Select	c.6094+1_6094+5delGTAAA		splice_donor splice_region intron	N/A	ENSP00000382576.3
	KNL1	ENST00000346991.9	TSL:1	c.6172+1_6172+5delGTAAA		splice_donor splice_region intron	N/A	ENSP00000335463.6
	KNL1	ENST00000526913.5	TSL:1	n.3226+1_3226+5delGTAAA		splice_donor splice_region intron	N/A	ENSP00000432565.1

Frequencies

GnomAD3 genomes AF: 0.000197 AC: 30 AN: 151992 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00114

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000317 AC: 78 AN: 246224 AF XY: 0.000359

Gnomad AFR exome AF: 0.0000650

Gnomad AMR exome AF: 0.0000904

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000744

Gnomad NFE exome AF: 0.000489

Gnomad OTH exome AF: 0.000501

GnomAD4 exome AF: 0.000236 AC: 298 AN: 1260872 Hom.: 0 AF XY: 0.000226 AC XY: 144 AN XY: 637440

African (AFR) AF: 0.00 AC: 0 AN: 29284

American (AMR) AF: 0.0000464 AC: 2 AN: 43118

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24804

East Asian (EAS) AF: 0.0000517 AC: 2 AN: 38664

South Asian (SAS) AF: 0.0000123 AC: 1 AN: 81572

European-Finnish (FIN) AF: 0.00104 AC: 55 AN: 53112

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5374

European-Non Finnish (NFE) AF: 0.000245 AC: 228 AN: 931144

Other (OTH) AF: 0.000186 AC: 10 AN: 53800

GnomAD4 genome AF: 0.000197 AC: 30 AN: 151992 Hom.: 0 Cov.: 31 AF XY: 0.000216 AC XY: 16 AN XY: 74218

African (AFR) AF: 0.0000242 AC: 1 AN: 41372

American (AMR) AF: 0.00 AC: 0 AN: 15244

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00114 AC: 12 AN: 10566

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000250 AC: 17 AN: 68006

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.000270 Hom.: 0

Bravo AF: 0.0000756

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		4.9
Mutation Taster		=34/66	disease causing

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs587780294; hg19: chr15-40939272;