chr15-40624434-T-A

Position:

chr15-40624434-T-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_144508.5(KNL1):c.4170T>A(p.Asp1390Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00119 in 1,613,996 control chromosomes in the GnomAD database, including 10 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 Likely benign (★★).

Frequency

Genomes: 𝑓 0.0016 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0011 ( 9 hom. )

Consequence

KNL1
NM_144508.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -0.0670

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:

KNL1 (HGNC:):

KNL1 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.002544582).

BP6

Variant 15-40624434-T-A is Benign according to our data. Variant chr15-40624434-T-A is described in ClinVar as [Likely_benign]. Clinvar id is 128599.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-40624434-T-A is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00162 (247/152328) while in subpopulation EAS AF= 0.0218 (113/5190). AF 95% confidence interval is 0.0185. There are 1 homozygotes in gnomad4. There are 126 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KNL1	NM_144508.5 linkuse as main transcript	c.4170T>A	p.Asp1390Glu	missense_variant	10/26	ENST00000399668.7	NP_653091.3	Q8NG31-2
KNL1	NM_170589.5 linkuse as main transcript	c.4248T>A	p.Asp1416Glu	missense_variant	11/27		NP_733468.3	Q8NG31-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KNL1	ENST00000399668.7 linkuse as main transcript	c.4170T>A	p.Asp1390Glu	missense_variant	10/26	1	NM_144508.5	ENSP00000382576.3		Q8NG31-2

Frequencies

GnomAD3 genomes

AF:

0.00166

AC:

252

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00615

Gnomad ASJ

AF:

0.00260

Gnomad EAS

AF:

0.0223

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.000282

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000338

Gnomad OTH

AF:

0.000956

GnomAD3 exomes

AF:

0.00382

AC:

953

AN:

249218

Hom.:

AF XY:

0.00304

AC XY:

411

AN XY:

135228

show subpopulations

Gnomad AFR exome

AF:

0.0000646

Gnomad AMR exome

AF:

0.0126

Gnomad ASJ exome

AF:

0.00397

Gnomad EAS exome

AF:

0.0226

Gnomad SAS exome

AF:

0.000360

Gnomad FIN exome

AF:

0.000326

Gnomad NFE exome

AF:

0.000389

Gnomad OTH exome

AF:

0.00165

GnomAD4 exome

AF:

0.00114

AC:

1673

AN:

1461668

Hom.:

Cov.:

AF XY:

0.00105

AC XY:

764

AN XY:

727126

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0114

Gnomad4 ASJ exome

AF:

0.00321

Gnomad4 EAS exome

AF:

0.0175

Gnomad4 SAS exome

AF:

0.000475

Gnomad4 FIN exome

AF:

0.000431

Gnomad4 NFE exome

AF:

0.000213

Gnomad4 OTH exome

AF:

0.00141

GnomAD4 genome

AF:

0.00162

AC:

247

AN:

152328

Hom.:

Cov.:

AF XY:

0.00169

AC XY:

126

AN XY:

74498

show subpopulations

Gnomad4 AFR

AF:

0.0000240

Gnomad4 AMR

AF:

0.00615

Gnomad4 ASJ

AF:

0.00260

Gnomad4 EAS

AF:

0.0218

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.000282

Gnomad4 NFE

AF:

0.000338

Gnomad4 OTH

AF:

0.000946

Alfa

AF:

0.00110

Hom.:

Bravo

AF:

0.00252

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000610

AC:

ExAC

AF:

0.00337

AC:

407

Asia WGS

AF:

0.00404

AC:

AN:

3478

EpiCase

AF:

0.000709

EpiControl

AF:

0.000296

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 29, 2019	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jan 06, 2016

- -

Microcephaly 4, primary, autosomal recessive

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.60

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.14

T;T;.

Eigen

Benign

0.084

Eigen_PC

Benign

0.041

FATHMM_MKL

Benign

0.17

LIST_S2

Benign

0.63

T;T;T

MetaRNN

Benign

0.0025

T;T;T

MetaSVM

Benign

-1.1

PrimateAI

Benign

0.37

PROVEAN

Benign

-2.0

N;.;N

REVEL

Benign

0.068

Sift

Pathogenic

0.0

D;.;D

Sift4G

Uncertain

0.022

D;D;D

Polyphen

0.88

P;.;P

Vest4

0.056

MutPred

0.31

Gain of methylation at K1419 (P = 0.0728);.;.;

MVP

0.45

MPC

0.045

ClinPred

0.048

GERP RS

4.0

Varity_R

0.30

gMVP

0.074

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