rs11070285

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_144508.5(KNL1):c.3432T>C(p.Asn1144Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.397 in 1,613,442 control chromosomes in the GnomAD database, including 129,233 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.39 ( 11803 hom., cov: 31)

Exomes 𝑓: 0.40 ( 117430 hom. )

Consequence

KNL1
NM_144508.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.00200

Publications

30 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.88).

BP6

Variant 15-40623696-T-C is Benign according to our data. Variant chr15-40623696-T-C is described in ClinVar as Benign. ClinVar VariationId is 128596.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.002 with no splicing effect.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.444 is higher than 0.05.

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.3432T>C	p.Asn1144Asn	synonymous	Exon 10 of 26	NP_653091.3
	KNL1	NM_170589.5		c.3510T>C	p.Asn1170Asn	synonymous	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.3432T>C	p.Asn1144Asn	synonymous	Exon 10 of 26	ENSP00000382576.3
KNL1	ENST00000346991.9	TSL:1	c.3510T>C	p.Asn1170Asn	synonymous	Exon 11 of 27	ENSP00000335463.6
KNL1	ENST00000526913.5	TSL:1	n.564T>C		non_coding_transcript_exon	Exon 1 of 18	ENSP00000432565.1

Frequencies

GnomAD3 genomes

AF:

0.391

AC:

59319

AN:

151704

Hom.:

11785

Cov.:

show subpopulations

Gnomad AFR

AF:

0.372

Gnomad AMI

AF:

0.391

Gnomad AMR

AF:

0.328

Gnomad ASJ

AF:

0.415

Gnomad EAS

AF:

0.247

Gnomad SAS

AF:

0.460

Gnomad FIN

AF:

0.470

Gnomad MID

AF:

0.481

Gnomad NFE

AF:

0.410

Gnomad OTH

AF:

0.371

GnomAD2 exomes

AF:

0.387

AC:

96278

AN:

248818

AF XY:

0.400

show subpopulations

Gnomad AFR exome

AF:

0.368

Gnomad AMR exome

AF:

0.259

Gnomad ASJ exome

AF:

0.426

Gnomad EAS exome

AF:

0.239

Gnomad FIN exome

AF:

0.460

Gnomad NFE exome

AF:

0.408

Gnomad OTH exome

AF:

0.399

GnomAD4 exome

AF:

0.397

AC:

580565

AN:

1461620

Hom.:

117430

Cov.:

AF XY:

0.402

AC XY:

292097

AN XY:

727116

show subpopulations

African (AFR)

AF:

0.372

AC:

12459

AN:

33472

American (AMR)

AF:

0.268

AC:

11979

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.419

AC:

10951

AN:

26128

East Asian (EAS)

AF:

0.250

AC:

9935

AN:

39690

South Asian (SAS)

AF:

0.494

AC:

42573

AN:

86256

European-Finnish (FIN)

AF:

0.458

AC:

24452

AN:

53384

Middle Eastern (MID)

AF:

0.444

AC:

2559

AN:

5768

European-Non Finnish (NFE)

AF:

0.397

AC:

441405

AN:

1111820

Other (OTH)

AF:

0.402

AC:

24252

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

20330

40661

60991

81322

101652

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

13590

27180

40770

54360

67950

<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:

0.391

AC:

59373

AN:

151822

Hom.:

11803

Cov.:

AF XY:

0.393

AC XY:

29182

AN XY:

74180

show subpopulations

African (AFR)

AF:

0.372

AC:

15394

AN:

41406

American (AMR)

AF:

0.328

AC:

5002

AN:

15240

Ashkenazi Jewish (ASJ)

AF:

0.415

AC:

1441

AN:

3470

East Asian (EAS)

AF:

0.246

AC:

1274

AN:

5170

South Asian (SAS)

AF:

0.460

AC:

2208

AN:

4800

European-Finnish (FIN)

AF:

0.470

AC:

4949

AN:

10528

Middle Eastern (MID)

AF:

0.469

AC:

138

AN:

294

European-Non Finnish (NFE)

AF:

0.410

AC:

27821

AN:

67898

Other (OTH)

AF:

0.375

AC:

790

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1802

3603

5405

7206

9008

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

580

1160

1740

2320

2900

<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:

0.397

Hom.:

9994

Bravo

AF:

0.374

Asia WGS

AF:

0.373

AC:

1297

AN:

3478

EpiCase

AF:

0.403

EpiControl

AF:

0.400

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Microcephaly 4, primary, autosomal recessive (1)

not specified (1)

Primary Microcephaly, Recessive (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.88

CADD

Benign

0.82

(source)

DANN

Benign

0.30

PhyloP100

0.0020

Mutation Taster

=100/0

polymorphism (auto)

(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

Computational scores

Splicing

Publications

Other links and lift over