Genetic Variant KNL1:p.Arg43Ile (chr15-40606445-G-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_144508.5(KNL1):c.128G>T(p.Arg43Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R43T) has been classified as Benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

KNL1
NM_144508.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.751

Publications

49 publications found

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 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

KNL1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.021760106).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KNL1	NM_144508.5 link	c.128G>T	p.Arg43Ile	missense_variant	Exon 4 of 26	ENST00000399668.7	NP_653091.3	Q8NG31-2
KNL1	NM_170589.5 link	c.128G>T	p.Arg43Ile	missense_variant	Exon 4 of 27		NP_733468.3	Q8NG31-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KNL1	ENST00000399668.7 link	c.128G>T	p.Arg43Ile	missense_variant	Exon 4 of 26	1	NM_144508.5	ENSP00000382576.3		Q8NG31-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

1393028

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

696386

African (AFR)

AF:

0.00

AC:

AN:

32316

American (AMR)

AF:

0.00

AC:

AN:

44566

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25608

East Asian (EAS)

AF:

0.00

AC:

AN:

39404

South Asian (SAS)

AF:

0.00

AC:

AN:

84612

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53264

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5500

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1049728

Other (OTH)

AF:

0.00

AC:

AN:

58030

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

38977

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.071

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.70

CADD

Benign

7.6

(source)

DANN

Benign

0.35

DEOGEN2

Benign

0.014

T;T;.

Eigen

Benign

-1.8

Eigen_PC

Benign

-1.8

FATHMM_MKL

Benign

0.0055

LIST_S2

Benign

0.20

T;T;T

M_CAP

Benign

0.0041

MetaRNN

Benign

0.022

T;T;T

MetaSVM

Benign

-1.0

PhyloP100

-0.75

PrimateAI

Benign

0.42

PROVEAN

Benign

0.33

N;N;N

REVEL

Benign

0.012

Sift

Benign

0.58

T;T;T

Sift4G

Benign

0.28

T;T;T

Polyphen

0.0

B;.;B

Vest4

0.089

MutPred

0.23

Gain of sheet (P = 0.0477);Gain of sheet (P = 0.0477);Gain of sheet (P = 0.0477);

MVP

0.13

MPC

0.054

ClinPred

0.038

GERP RS

-4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.040

gMVP

0.14

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over