rs187007187

Positions:

chr15-40624643-T-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The ENST00000399668.7(KNL1):c.4379T>C(p.Ile1460Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000298 in 1,613,886 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0015 ( 2 hom., cov: 32)

Exomes 𝑓: 0.00017 ( 1 hom. )

Consequence

KNL1
ENST00000399668.7 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 0.488

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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.004510492).

BP6

Variant 15-40624643-T-C is Benign according to our data. Variant chr15-40624643-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 128602.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}. Variant chr15-40624643-T-C is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00153 (233/152266) while in subpopulation AFR AF= 0.00549 (228/41554). AF 95% confidence interval is 0.0049. There are 2 homozygotes in gnomad4. There are 101 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KNL1	NM_144508.5 linkuse as main transcript	c.4379T>C	p.Ile1460Thr	missense_variant	10/26	ENST00000399668.7	NP_653091.3
KNL1	NM_170589.5 linkuse as main transcript	c.4457T>C	p.Ile1486Thr	missense_variant	11/27		NP_733468.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KNL1	ENST00000399668.7 linkuse as main transcript	c.4379T>C	p.Ile1460Thr	missense_variant	10/26	1	NM_144508.5	ENSP00000382576	A2	Q8NG31-2

Frequencies

GnomAD3 genomes

AF:

0.00152

AC:

232

AN:

152148

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00548

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000197

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000957

GnomAD3 exomes

AF:

0.000345

AC:

AN:

249170

Hom.:

AF XY:

0.000222

AC XY:

AN XY:

135258

show subpopulations

Gnomad AFR exome

AF:

0.00524

Gnomad AMR exome

AF:

0.0000871

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000884

Gnomad OTH exome

AF:

0.000166

GnomAD4 exome

AF:

0.000170

AC:

248

AN:

1461620

Hom.:

Cov.:

AF XY:

0.000140

AC XY:

102

AN XY:

727122

show subpopulations

Gnomad4 AFR exome

AF:

0.00669

Gnomad4 AMR exome

AF:

0.000134

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.000265

GnomAD4 genome

AF:

0.00153

AC:

233

AN:

152266

Hom.:

Cov.:

AF XY:

0.00136

AC XY:

101

AN XY:

74442

show subpopulations

Gnomad4 AFR

AF:

0.00549

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000947

Alfa

AF:

0.000251

Hom.:

Bravo

AF:

0.00182

ESP6500AA

AF:

0.00494

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000389

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jul 30, 2013	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.64

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.040

T;T;.

Eigen

Benign

-0.96

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.054

LIST_S2

Benign

0.47

T;T;T

M_CAP

Benign

0.0052

MetaRNN

Benign

0.0045

T;T;T

MetaSVM

Benign

-0.96

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.33

PROVEAN

Benign

-1.1

N;.;N

REVEL

Benign

0.031

Sift

Benign

0.043

D;.;D

Sift4G

Uncertain

0.032

D;T;D

Polyphen

0.19

B;.;B

Vest4

0.10

MVP

0.20

MPC

0.057

ClinPred

0.0037

GERP RS

-2.1

Varity_R

0.027

gMVP

0.044

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