15-40624434-T-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -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. 13/20 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

Publications

7 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 (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 Benign/Likely_benign. ClinVar VariationId is 128599.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 9 AR gene

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KNL1	NM_144508.5	MANE Select	c.4170T>A	p.Asp1390Glu	missense	Exon 10 of 26	NP_653091.3
	KNL1	NM_170589.5		c.4248T>A	p.Asp1416Glu	missense	Exon 11 of 27	NP_733468.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
KNL1	ENST00000399668.7	TSL:1 MANE Select	c.4170T>A	p.Asp1390Glu	missense	Exon 10 of 26	ENSP00000382576.3
KNL1	ENST00000346991.9	TSL:1	c.4248T>A	p.Asp1416Glu	missense	Exon 11 of 27	ENSP00000335463.6
KNL1	ENST00000526913.5	TSL:1	n.1302T>A		non_coding_transcript_exon	Exon 1 of 18	ENSP00000432565.1

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

GnomAD2 exomes

AF:

0.00382

AC:

953

AN:

249218

AF XY:

0.00304

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 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

African (AFR)

AF:

0.00

AC:

AN:

33476

American (AMR)

AF:

0.0114

AC:

509

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00321

AC:

AN:

26128

East Asian (EAS)

AF:

0.0175

AC:

693

AN:

39684

South Asian (SAS)

AF:

0.000475

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.000431

AC:

AN:

53326

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.000213

AC:

237

AN:

1111924

Other (OTH)

AF:

0.00141

AC:

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

111

222

332

443

554

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

112

140

<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:

0.00162

AC:

247

AN:

152328

Hom.:

Cov.:

AF XY:

0.00169

AC XY:

126

AN XY:

74498

show subpopulations

African (AFR)

AF:

0.0000240

AC:

AN:

41594

American (AMR)

AF:

0.00615

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00260

AC:

AN:

3464

East Asian (EAS)

AF:

0.0218

AC:

113

AN:

5190

South Asian (SAS)

AF:

0.000207

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.000282

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000338

AC:

AN:

68008

Other (OTH)

AF:

0.000946

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

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:

0.00110

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

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Dec 29, 2019

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not specified

Benign:1

Jan 06, 2016

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Microcephaly 4, primary, autosomal recessive

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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 v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.60

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.14

Eigen

Benign

0.084

Eigen_PC

Benign

0.041

FATHMM_MKL

Benign

0.17

LIST_S2

Benign

0.63

MetaRNN

Benign

0.0025

MetaSVM

Benign

-1.1

PhyloP100

-0.067

PrimateAI

Benign

0.37

PROVEAN

Benign

-2.0

REVEL

Benign

0.068

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.022

Polyphen

0.88

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

Mutation Taster

=100/0

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

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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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over