ENST00000526913.5:n.*1434A>C – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The ENST00000526913.5(KNL1):n.*1434A>C variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.253 in 176,550 control chromosomes in the GnomAD database, including 6,791 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.25 ( 5780 hom., cov: 32)

Exomes 𝑓: 0.27 ( 1011 hom. )

Consequence

KNL1
ENST00000526913.5 non_coding_transcript_exon

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.845

Publications

13 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 -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.86).

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.331 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KNL1	NM_144508.5 link	c.*2085A>C		3_prime_UTR_variant	Exon 26 of 26	ENST00000399668.7	NP_653091.3	Q8NG31-2
KNL1	NM_170589.5 link	c.*2085A>C		3_prime_UTR_variant	Exon 27 of 27		NP_733468.3	Q8NG31-1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
KNL1	ENST00000526913.5 link	n.*1434A>C	non_coding_transcript_exon_variant	Exon 18 of 18	1		ENSP00000432565.1	H0YCZ2
KNL1	ENST00000399668.7 link	c.*2085A>C	3_prime_UTR_variant	Exon 26 of 26	1	NM_144508.5	ENSP00000382576.3	Q8NG31-2
KNL1	ENST00000346991.9 link	c.*2085A>C	3_prime_UTR_variant	Exon 27 of 27	1		ENSP00000335463.6	Q8NG31-1
KNL1	ENST00000526913.5 link	n.*1434A>C	3_prime_UTR_variant	Exon 18 of 18	1		ENSP00000432565.1	H0YCZ2

Frequencies

GnomAD3 genomes

AF:

0.249

AC:

37854

AN:

151926

Hom.:

5775

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0760

Gnomad AMI

AF:

0.332

Gnomad AMR

AF:

0.247

Gnomad ASJ

AF:

0.356

Gnomad EAS

AF:

0.102

Gnomad SAS

AF:

0.344

Gnomad FIN

AF:

0.364

Gnomad MID

AF:

0.370

Gnomad NFE

AF:

0.335

Gnomad OTH

AF:

0.252

GnomAD4 exome

AF:

0.275

AC:

6729

AN:

24506

Hom.:

1011

Cov.:

AF XY:

0.278

AC XY:

3098

AN XY:

11150

show subpopulations

African (AFR)

AF:

0.0835

AC:

AN:

790

American (AMR)

AF:

0.226

AC:

120

AN:

532

Ashkenazi Jewish (ASJ)

AF:

0.360

AC:

542

AN:

1506

East Asian (EAS)

AF:

0.140

AC:

743

AN:

5320

South Asian (SAS)

AF:

0.374

AC:

AN:

190

European-Finnish (FIN)

AF:

0.286

AC:

AN:

Middle Eastern (MID)

AF:

0.304

AC:

AN:

138

European-Non Finnish (NFE)

AF:

0.324

AC:

4542

AN:

14026

Other (OTH)

AF:

0.301

AC:

599

AN:

1990

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

207

413

620

826

1033

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

104

130

<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:

0.249

AC:

37858

AN:

152044

Hom.:

5780

Cov.:

AF XY:

0.253

AC XY:

18776

AN XY:

74298

show subpopulations

African (AFR)

AF:

0.0758

AC:

3147

AN:

41506

American (AMR)

AF:

0.247

AC:

3767

AN:

15242

Ashkenazi Jewish (ASJ)

AF:

0.356

AC:

1235

AN:

3466

East Asian (EAS)

AF:

0.103

AC:

532

AN:

5190

South Asian (SAS)

AF:

0.344

AC:

1660

AN:

4826

European-Finnish (FIN)

AF:

0.364

AC:

3830

AN:

10532

Middle Eastern (MID)

AF:

0.371

AC:

109

AN:

294

European-Non Finnish (NFE)

AF:

0.334

AC:

22737

AN:

67974

Other (OTH)

AF:

0.256

AC:

541

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1369

2737

4106

5474

6843

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

392

784

1176

1568

1960

<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:

0.273

Hom.:

4981

Bravo

AF:

0.227

Asia WGS

AF:

0.241

AC:

837

AN:

3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.86

CADD

Benign

0.48

(source)

DANN

Benign

0.48

PhyloP100

-0.84

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over