chr15-40603101-A-T

Variant names:

• chr15-40603101-A-T
• rs189663662
• NM_144508.5:c.35+135A>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_144508.5(KNL1):​c.35+135A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00512 in 543,212 control chromosomes in the GnomAD database, including 56 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.013 (44 hom., cov: 32)
  • Exomes 𝑓: 0.0020 (12 hom.)
• Consequence: KNL1 NM_144508.5 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.735
• Publications: 0 publications found

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

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 15-40603101-A-T is Benign according to our data. Variant chr15-40603101-A-T is described in ClinVar as [Likely_benign]. Clinvar id is 1185905.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0133 (2012/150926) while in subpopulation AFR AF = 0.0458 (1886/41202). AF 95% confidence interval is 0.0441. There are 44 homozygotes in GnomAd4. There are 961 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 44 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KNL1	NM_144508.5	c.35+135A>T		intron_variant	Intron 2 of 25	ENST00000399668.7	NP_653091.3
KNL1	NM_170589.5	c.35+135A>T		intron_variant	Intron 2 of 26		NP_733468.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KNL1	ENST00000399668.7	c.35+135A>T		intron_variant	Intron 2 of 25	1	NM_144508.5	ENSP00000382576.3

Frequencies

GnomAD3 genomes AF: 0.0133 AC: 2000 AN: 150810 Hom.: 43 Cov.: 32

Gnomad AFR AF: 0.0456

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00501

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000834

Gnomad FIN AF: 0.0000988

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000340

Gnomad OTH AF: 0.00768

GnomAD4 exome AF: 0.00196 AC: 770 AN: 392286 Hom.: 12 AF XY: 0.00182 AC XY: 384 AN XY: 210996

African (AFR) AF: 0.0465 AC: 453 AN: 9752

American (AMR) AF: 0.00310 AC: 42 AN: 13536

Ashkenazi Jewish (ASJ) AF: 0.00294 AC: 33 AN: 11228

East Asian (EAS) AF: 0.000649 AC: 16 AN: 24652

South Asian (SAS) AF: 0.000620 AC: 25 AN: 40294

European-Finnish (FIN) AF: 0.000326 AC: 8 AN: 24532

Middle Eastern (MID) AF: 0.00617 AC: 10 AN: 1622

European-Non Finnish (NFE) AF: 0.000359 AC: 88 AN: 245314

Other (OTH) AF: 0.00445 AC: 95 AN: 21356

GnomAD4 genome AF: 0.0133 AC: 2012 AN: 150926 Hom.: 44 Cov.: 32 AF XY: 0.0130 AC XY: 961 AN XY: 73700

African (AFR) AF: 0.0458 AC: 1886 AN: 41202

American (AMR) AF: 0.00500 AC: 76 AN: 15204

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3462

East Asian (EAS) AF: 0.00 AC: 0 AN: 5158

South Asian (SAS) AF: 0.000835 AC: 4 AN: 4792

European-Finnish (FIN) AF: 0.0000988 AC: 1 AN: 10124

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000340 AC: 23 AN: 67678

Other (OTH) AF: 0.00760 AC: 16 AN: 2104

Alfa AF: 0.00953 Hom.: 2

Bravo AF: 0.0157

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Apr 20, 2019

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.64
DANN	Benign	0.68
PhyloP100		0.73
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs189663662; hg19: chr15-40895299; COSMIC: COSV61162259;