rs1051482

Positions:

• chr15-40664273-A-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_144508.5(KNL1):​c.*2085A>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.253 in 176,550 control chromosomes in the GnomAD database, including 6,791 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 0.25 (5780 hom., cov: 32)
  • Exomes 𝑓: 0.27 (1011 hom.)
• Consequence: KNL1 NM_144508.5 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.845

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.331 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KNL1	NM_144508.5	c.*2085A>C		3_prime_UTR_variant	26/26	ENST00000399668.7	NP_653091.3
KNL1	NM_170589.5	c.*2085A>C		3_prime_UTR_variant	27/27		NP_733468.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KNL1	ENST00000399668.7	c.*2085A>C		3_prime_UTR_variant	26/26	1	NM_144508.5	ENSP00000382576	A2
KNL1	ENST00000346991.9	c.*2085A>C		3_prime_UTR_variant	27/27	1		ENSP00000335463	P4
KNL1	ENST00000526913.5	c.*1434A>C		3_prime_UTR_variant, NMD_transcript_variant	18/18	1		ENSP00000432565

Frequencies

GnomAD3 genomes AF: 0.249 AC: 37854 AN: 151926 Hom.: 5775 Cov.: 32

Gnomad AFR AF: 0.0760

Gnomad AMI AF: 0.332

Gnomad AMR AF: 0.247

Gnomad ASJ AF: 0.356

Gnomad EAS AF: 0.102

Gnomad SAS AF: 0.344

Gnomad FIN AF: 0.364

Gnomad MID AF: 0.370

Gnomad NFE AF: 0.335

Gnomad OTH AF: 0.252

GnomAD4 exome AF: 0.275 AC: 6729 AN: 24506 Hom.: 1011 Cov.: 0 AF XY: 0.278 AC XY: 3098 AN XY: 11150

Gnomad4 AFR exome AF: 0.0835

Gnomad4 AMR exome AF: 0.226

Gnomad4 ASJ exome AF: 0.360

Gnomad4 EAS exome AF: 0.140

Gnomad4 SAS exome AF: 0.374

Gnomad4 FIN exome AF: 0.286

Gnomad4 NFE exome AF: 0.324

Gnomad4 OTH exome AF: 0.301

GnomAD4 genome AF: 0.249 AC: 37858 AN: 152044 Hom.: 5780 Cov.: 32 AF XY: 0.253 AC XY: 18776 AN XY: 74298

Gnomad4 AFR AF: 0.0758

Gnomad4 AMR AF: 0.247

Gnomad4 ASJ AF: 0.356

Gnomad4 EAS AF: 0.103

Gnomad4 SAS AF: 0.344

Gnomad4 FIN AF: 0.364

Gnomad4 NFE AF: 0.334

Gnomad4 OTH AF: 0.256

Alfa AF: 0.319 Hom.: 3712

Bravo AF: 0.227

Asia WGS AF: 0.241 AC: 837 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.48
DANN	Benign	0.48

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: rs1051482; hg19: chr15-40956471;