rs11858113

Positions:

chr15-40621979-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_144508.5(KNL1):c.1715T>C(p.Met572Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.396 in 1,613,456 control chromosomes in the GnomAD database, including 128,915 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.39 ( 11805 hom., cov: 32)

Exomes 𝑓: 0.40 ( 117110 hom. )

Consequence

KNL1
NM_144508.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 1.52

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0021754205).

BP6

Variant 15-40621979-T-C is Benign according to our data. Variant chr15-40621979-T-C is described in ClinVar as [Benign]. Clinvar id is 128589.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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/exons	MANE	UniProt
KNL1	NM_144508.5 linkuse as main transcript	c.1715T>C	p.Met572Thr	missense_variant	10/26	ENST00000399668.7
KNL1	NM_170589.5 linkuse as main transcript	c.1793T>C	p.Met598Thr	missense_variant	11/27

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KNL1	ENST00000399668.7 linkuse as main transcript	c.1715T>C	p.Met572Thr	missense_variant	10/26	1	NM_144508.5	A2	Q8NG31-2

Frequencies

GnomAD3 genomes

AF:

0.391

AC:

59385

AN:

151990

Hom.:

11787

Cov.:

show subpopulations

Gnomad AFR

AF:

0.373

Gnomad AMI

AF:

0.394

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:

0.370

GnomAD3 exomes

AF:

0.386

AC:

96131

AN:

248854

Hom.:

19533

AF XY:

0.399

AC XY:

53865

AN XY:

135030

show subpopulations

Gnomad AFR exome

AF:

0.369

Gnomad AMR exome

AF:

0.258

Gnomad ASJ exome

AF:

0.417

Gnomad EAS exome

AF:

0.239

Gnomad SAS exome

AF:

0.484

Gnomad FIN exome

AF:

0.461

Gnomad NFE exome

AF:

0.407

Gnomad OTH exome

AF:

0.397

GnomAD4 exome

AF:

0.397

AC:

579650

AN:

1461348

Hom.:

117110

Cov.:

AF XY:

0.401

AC XY:

291601

AN XY:

726978

show subpopulations

Gnomad4 AFR exome

AF:

0.373

Gnomad4 AMR exome

AF:

0.267

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:

0.391

AC:

59439

AN:

152108

Hom.:

11805

Cov.:

AF XY:

0.393

AC XY:

29216

AN XY:

74354

show subpopulations

Gnomad4 AFR

AF:

0.373

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:

0.374

Alfa

AF:

0.399

Hom.:

30313

Bravo

AF:

0.374

TwinsUK

AF:

0.399

AC:

1480

ALSPAC

AF:

0.400

AC:

1541

ESP6500AA

AF:

0.368

AC:

1375

ESP6500EA

AF:

0.402

AC:

3307

ExAC

AF:

0.392

AC:

47340

Asia WGS

AF:

0.374

AC:

1302

AN:

3478

EpiCase

AF:

0.401

EpiControl

AF:

0.398

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 20, 2018	- -

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

- -

Microcephaly 4, primary, autosomal recessive

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.69

BayesDel_noAF

Benign

-0.62

CADD

Benign

DANN

Benign

0.88

DEOGEN2

Benign

0.32

T;T;.

Eigen

Benign

-0.45

Eigen_PC

Benign

-0.47

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.38

T;T;T

MetaRNN

Benign

0.0022

T;T;T

MetaSVM

Benign

-0.94

MutationTaster

Benign

0.97

P;P;P

PrimateAI

Benign

0.28

PROVEAN

Uncertain

-2.9

D;.;D

REVEL

Benign

0.13

Sift

Benign

0.20

T;.;T

Sift4G

Uncertain

0.0080

D;D;D

Polyphen

0.88

P;.;B

Vest4

0.33

MPC

0.041

ClinPred

0.025

GERP RS

0.77

Varity_R

0.14

gMVP

0.41

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over