rs74363042

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_144508.5(KNL1):c.135+138G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0501 in 531,594 control chromosomes in the GnomAD database, including 842 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.042 ( 168 hom., cov: 32)

Exomes 𝑓: 0.053 ( 674 hom. )

Consequence

KNL1
NM_144508.5 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.108

Publications

2 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: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.9).

BP6

Variant 15-40606590-G-A is Benign according to our data. Variant chr15-40606590-G-A is described in ClinVar as [Benign]. Clinvar id is 1256682.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.11 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KNL1	NM_144508.5 link	c.135+138G>A		intron_variant	Intron 4 of 25	ENST00000399668.7	NP_653091.3	Q8NG31-2
KNL1	NM_170589.5 link	c.135+138G>A		intron_variant	Intron 4 of 26		NP_733468.3	Q8NG31-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KNL1	ENST00000399668.7 link	c.135+138G>A		intron_variant	Intron 4 of 25	1	NM_144508.5	ENSP00000382576.3		Q8NG31-2

Frequencies

GnomAD3 genomes

AF:

0.0421

AC:

6399

AN:

152096

Hom.:

166

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00857

Gnomad AMI

AF:

0.0407

Gnomad AMR

AF:

0.0405

Gnomad ASJ

AF:

0.0187

Gnomad EAS

AF:

0.118

Gnomad SAS

AF:

0.107

Gnomad FIN

AF:

0.0591

Gnomad MID

AF:

0.0316

Gnomad NFE

AF:

0.0511

Gnomad OTH

AF:

0.0398

GnomAD4 exome

AF:

0.0533

AC:

20208

AN:

379380

Hom.:

674

AF XY:

0.0550

AC XY:

10879

AN XY:

197974

show subpopulations

African (AFR)

AF:

0.00830

AC:

AN:

11090

American (AMR)

AF:

0.0433

AC:

755

AN:

17436

Ashkenazi Jewish (ASJ)

AF:

0.0169

AC:

200

AN:

11844

East Asian (EAS)

AF:

0.0905

AC:

2698

AN:

29822

South Asian (SAS)

AF:

0.0904

AC:

2381

AN:

26342

European-Finnish (FIN)

AF:

0.0583

AC:

2320

AN:

39824

Middle Eastern (MID)

AF:

0.0263

AC:

AN:

1634

European-Non Finnish (NFE)

AF:

0.0485

AC:

10679

AN:

220024

Other (OTH)

AF:

0.0487

AC:

1040

AN:

21364

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

856

1711

2567

3422

4278

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0421

AC:

6401

AN:

152214

Hom.:

168

Cov.:

AF XY:

0.0439

AC XY:

3265

AN XY:

74426

show subpopulations

African (AFR)

AF:

0.00855

AC:

355

AN:

41536

American (AMR)

AF:

0.0408

AC:

624

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.0187

AC:

AN:

3468

East Asian (EAS)

AF:

0.118

AC:

611

AN:

5184

South Asian (SAS)

AF:

0.107

AC:

516

AN:

4818

European-Finnish (FIN)

AF:

0.0591

AC:

626

AN:

10594

Middle Eastern (MID)

AF:

0.0238

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0511

AC:

3475

AN:

68006

Other (OTH)

AF:

0.0403

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

337

675

1012

1350

1687

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0501

Hom.:

Bravo

AF:

0.0390

Asia WGS

AF:

0.0910

AC:

315

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jul 26, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

0.56

(source)

DANN

Benign

0.19

PhyloP100

-0.11

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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

rs74363042

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over