rs8041534

Positions:

• chr15-40622847-T-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_144508.5(KNL1):​c.2583T>G​(p.Thr861=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.396 in 1,612,450 control chromosomes in the GnomAD database, including 128,798 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.39 (11755 hom., cov: 32)
  • Exomes 𝑓: 0.40 (117043 hom.)
• Consequence: KNL1 NM_144508.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.289

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BP6: Variant 15-40622847-T-G is Benign according to our data. Variant chr15-40622847-T-G is described in ClinVar as [Benign]. Clinvar id is 128593.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.289 with no splicing effect.
• 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	Protein	UniProt
KNL1	NM_144508.5	c.2583T>G	p.Thr861=	synonymous_variant	10/26	ENST00000399668.7	NP_653091.3
KNL1	NM_170589.5	c.2661T>G	p.Thr887=	synonymous_variant	11/27		NP_733468.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KNL1	ENST00000399668.7	c.2583T>G	p.Thr861=	synonymous_variant	10/26	1	NM_144508.5	ENSP00000382576	A2

Frequencies

GnomAD3 genomes AF: 0.390 AC: 59220 AN: 151888 Hom.: 11740 Cov.: 32

Gnomad AFR AF: 0.370

Gnomad AMI AF: 0.393

Gnomad AMR AF: 0.328

Gnomad ASJ AF: 0.405

Gnomad EAS AF: 0.246

Gnomad SAS AF: 0.460

Gnomad FIN AF: 0.469

Gnomad MID AF: 0.481

Gnomad NFE AF: 0.409

Gnomad OTH AF: 0.369

GnomAD3 exomes AF: 0.386 AC: 95945 AN: 248550 Hom.: 19520 AF XY: 0.399 AC XY: 53797 AN XY: 134898

Gnomad AFR exome AF: 0.367

Gnomad AMR exome AF: 0.257

Gnomad ASJ exome AF: 0.416

Gnomad EAS exome AF: 0.239

Gnomad SAS exome AF: 0.485

Gnomad FIN exome AF: 0.460

Gnomad NFE exome AF: 0.407

Gnomad OTH exome AF: 0.396

GnomAD4 exome AF: 0.397 AC: 579113 AN: 1460444 Hom.: 117043 Cov.: 42 AF XY: 0.401 AC XY: 291362 AN XY: 726558

Gnomad4 AFR exome AF: 0.370

Gnomad4 AMR exome AF: 0.266

Gnomad4 ASJ exome AF: 0.410

Gnomad4 EAS exome AF: 0.250

Gnomad4 SAS exome AF: 0.493

Gnomad4 FIN exome AF: 0.458

Gnomad4 NFE exome AF: 0.397

Gnomad4 OTH exome AF: 0.400

GnomAD4 genome AF: 0.390 AC: 59271 AN: 152006 Hom.: 11755 Cov.: 32 AF XY: 0.392 AC XY: 29132 AN XY: 74278

Gnomad4 AFR AF: 0.370

Gnomad4 AMR AF: 0.328

Gnomad4 ASJ AF: 0.405

Gnomad4 EAS AF: 0.246

Gnomad4 SAS AF: 0.460

Gnomad4 FIN AF: 0.469

Gnomad4 NFE AF: 0.409

Gnomad4 OTH AF: 0.373

Alfa AF: 0.397 Hom.: 15546

Bravo AF: 0.373

Asia WGS AF: 0.373 AC: 1296 AN: 3478

EpiCase AF: 0.402

EpiControl AF: 0.398

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Microcephaly 4, primary, autosomal recessive Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Apr 25, 2013

- -

Primary Microcephaly, Recessive Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	8.0
DANN	Benign	0.51
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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: rs8041534; hg19: chr15-40915045; COSMIC: COSV61152693; COSMIC: COSV61152693;