rs113313996

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_144508.5(KNL1):c.1214A>G(p.Asp405Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00045 in 1,613,858 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00032 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00046 ( 0 hom. )

Consequence

KNL1
NM_144508.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:5

Conservation

PhyloP100: 1.63

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: Labcorp Genetics (formerly Invitae), Ambry Genetics
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 -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.017874599).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_144508.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KNL1	NM_144508.5	MANE Select	c.1214A>G	p.Asp405Gly	missense	Exon 10 of 26	NP_653091.3	Q8NG31-2
	KNL1	NM_170589.5		c.1292A>G	p.Asp431Gly	missense	Exon 11 of 27	NP_733468.3	Q8NG31-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
KNL1	ENST00000399668.7	TSL:1 MANE Select	c.1214A>G	p.Asp405Gly	missense	Exon 10 of 26	ENSP00000382576.3	Q8NG31-2
KNL1	ENST00000346991.9	TSL:1	c.1292A>G	p.Asp431Gly	missense	Exon 11 of 27	ENSP00000335463.6	Q8NG31-1
KNL1	ENST00000533001.1	TSL:1	n.1359A>G		non_coding_transcript_exon	Exon 10 of 10

Frequencies

GnomAD3 genomes

AF:

0.000315

AC:

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00122

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000485

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000270

AC:

AN:

248470

AF XY:

0.000237

show subpopulations

Gnomad AFR exome

AF:

0.0000649

Gnomad AMR exome

AF:

0.0000580

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000557

Gnomad NFE exome

AF:

0.000463

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000464

AC:

678

AN:

1461652

Hom.:

Cov.:

AF XY:

0.000413

AC XY:

300

AN XY:

727126

show subpopulations

African (AFR)

AF:

0.0000597

AC:

AN:

33476

American (AMR)

AF:

0.0000447

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26128

East Asian (EAS)

AF:

0.00

AC:

AN:

39676

South Asian (SAS)

AF:

0.00

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.000975

AC:

AN:

53340

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.000528

AC:

587

AN:

1111900

Other (OTH)

AF:

0.000580

AC:

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

109

146

182

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

120

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000315

AC:

AN:

152206

Hom.:

Cov.:

AF XY:

0.000296

AC XY:

AN XY:

74368

show subpopulations

African (AFR)

AF:

0.0000482

AC:

AN:

41460

American (AMR)

AF:

0.00

AC:

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3464

East Asian (EAS)

AF:

0.00

AC:

AN:

5206

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00122

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000485

AC:

AN:

68022

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000485

Hom.:

Bravo

AF:

0.000253

ESP6500AA

AF:

0.000274

AC:

ESP6500EA

AF:

0.000368

AC:

ExAC

AF:

0.000273

AC:

EpiCase

AF:

0.000545

EpiControl

AF:

0.000474

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Inborn genetic diseases (1)

Microcephaly 4, primary, autosomal recessive (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.52

CADD

Benign

9.0

(source)

DANN

Benign

0.76

DEOGEN2

Benign

0.20

Eigen

Benign

-0.82

Eigen_PC

Benign

-0.81

FATHMM_MKL

Benign

0.14

LIST_S2

Benign

0.65

M_CAP

Benign

0.0045

MetaRNN

Benign

0.018

MetaSVM

Benign

-0.98

PhyloP100

1.6

PrimateAI

Benign

0.26

PROVEAN

Uncertain

-2.7

REVEL

Benign

0.049

Sift

Benign

0.061

Sift4G

Benign

0.60

Polyphen

0.0040

Vest4

0.20

MVP

0.22

MPC

0.046

ClinPred

0.041

GERP RS

2.8

Varity_R

0.11

gMVP

0.28

Mutation Taster

=94/6

polymorphism

(source)

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

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over