rs12911738

Positions:

Variant summary

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

The NM_144508.5(KNL1):c.259A>G(p.Thr87Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.801 in 229,010 control chromosomes in the GnomAD database, including 75,673 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.83 ( 53115 hom., cov: 32)

Exomes 𝑓: 0.75 ( 22558 hom. )

Consequence

KNL1
NM_144508.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.755

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=1.0240715E-6).

BP6

Variant 15-40611486-A-G is Benign according to our data. Variant chr15-40611486-A-G is described in ClinVar as [Benign]. Clinvar id is 128595.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.906 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KNL1	NM_144508.5 linkuse as main transcript	c.259A>G	p.Thr87Ala	missense_variant	7/26	ENST00000399668.7	NP_653091.3
KNL1	NM_170589.5 linkuse as main transcript	c.337A>G	p.Thr113Ala	missense_variant	8/27		NP_733468.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KNL1	ENST00000399668.7 linkuse as main transcript	c.259A>G	p.Thr87Ala	missense_variant	7/26	1	NM_144508.5	ENSP00000382576	A2	Q8NG31-2

Frequencies

GnomAD3 genomes

AF:

0.826

AC:

125524

AN:

151954

Hom.:

53068

Cov.:

show subpopulations

Gnomad AFR

AF:

0.914

Gnomad AMI

AF:

0.763

Gnomad AMR

AF:

0.673

Gnomad ASJ

AF:

0.806

Gnomad EAS

AF:

0.324

Gnomad SAS

AF:

0.727

Gnomad FIN

AF:

0.846

Gnomad MID

AF:

0.854

Gnomad NFE

AF:

0.852

Gnomad OTH

AF:

0.807

GnomAD3 exomes

AF:

0.785

AC:

26011

AN:

33116

Hom.:

10432

AF XY:

0.773

AC XY:

13355

AN XY:

17288

show subpopulations

Gnomad AFR exome

AF:

0.899

Gnomad AMR exome

AF:

0.511

Gnomad ASJ exome

AF:

0.743

Gnomad EAS exome

AF:

0.320

Gnomad SAS exome

AF:

0.635

Gnomad FIN exome

AF:

0.844

Gnomad NFE exome

AF:

0.809

Gnomad OTH exome

AF:

0.745

GnomAD4 exome

AF:

0.751

AC:

57811

AN:

76938

Hom.:

22558

Cov.:

AF XY:

0.747

AC XY:

28683

AN XY:

38372

show subpopulations

Gnomad4 AFR exome

AF:

0.827

Gnomad4 AMR exome

AF:

0.374

Gnomad4 ASJ exome

AF:

0.690

Gnomad4 EAS exome

AF:

0.119

Gnomad4 SAS exome

AF:

0.648

Gnomad4 FIN exome

AF:

0.843

Gnomad4 NFE exome

AF:

0.754

Gnomad4 OTH exome

AF:

0.687

GnomAD4 genome

AF:

0.826

AC:

125619

AN:

152072

Hom.:

53115

Cov.:

AF XY:

0.819

AC XY:

60873

AN XY:

74348

show subpopulations

Gnomad4 AFR

AF:

0.914

Gnomad4 AMR

AF:

0.672

Gnomad4 ASJ

AF:

0.806

Gnomad4 EAS

AF:

0.323

Gnomad4 SAS

AF:

0.727

Gnomad4 FIN

AF:

0.846

Gnomad4 NFE

AF:

0.852

Gnomad4 OTH

AF:

0.806

Alfa

AF:

0.847

Hom.:

58749

Bravo

AF:

0.808

TwinsUK

AF:

0.850

AC:

3150

ALSPAC

AF:

0.845

AC:

3257

ExAC

AF:

0.756

AC:

14833

Asia WGS

AF:

0.556

AC:

1932

AN:

3470

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Mar 24, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 17, 2016	- -

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 07, 2018	- -

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

0.063

BayesDel_addAF

Benign

-0.70

BayesDel_noAF

Benign

-0.64

CADD

Benign

4.9

DANN

Benign

0.85

DEOGEN2

Benign

0.014

T;T;.

Eigen

Benign

-0.97

Eigen_PC

Benign

-0.77

FATHMM_MKL

Benign

0.0035

LIST_S2

Benign

0.15

T;T;T

MetaRNN

Benign

0.0000010

T;T;T

MetaSVM

Benign

-0.99

MutationTaster

Benign

1.0

P;P;P

PrimateAI

Benign

0.35

PROVEAN

Benign

0.77

N;.;N

REVEL

Benign

0.075

Sift

Benign

1.0

T;.;T

Sift4G

Benign

1.0

T;T;T

Polyphen

0.0

B;.;B

Vest4

0.045

MPC

0.037

ClinPred

0.00063

GERP RS

3.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.037

gMVP

0.050

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.11

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