NM_144508.5:c.135+138G>A

Variant names:

• chr15-40606590-G-A
• rs74363042
• NM_144508.5:c.135+138G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_144508.5(KNL1):​c.135+138G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0501 in 531,594 control chromosomes in the GnomAD database, including 842 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.042 (168 hom., cov: 32)
  • Exomes 𝑓: 0.053 (674 hom.)
• Consequence: KNL1 NM_144508.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.108
• Publications: 2 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 15-40606590-G-A is Benign according to our data. Variant chr15-40606590-G-A is described in ClinVar as [Benign]. Clinvar id is 1256682.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.11 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KNL1	NM_144508.5	c.135+138G>A		intron_variant	Intron 4 of 25	ENST00000399668.7	NP_653091.3
KNL1	NM_170589.5	c.135+138G>A		intron_variant	Intron 4 of 26		NP_733468.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KNL1	ENST00000399668.7	c.135+138G>A		intron_variant	Intron 4 of 25	1	NM_144508.5	ENSP00000382576.3

Frequencies

GnomAD3 genomes AF: 0.0421 AC: 6399 AN: 152096 Hom.: 166 Cov.: 32

Gnomad AFR AF: 0.00857

Gnomad AMI AF: 0.0407

Gnomad AMR AF: 0.0405

Gnomad ASJ AF: 0.0187

Gnomad EAS AF: 0.118

Gnomad SAS AF: 0.107

Gnomad FIN AF: 0.0591

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0511

Gnomad OTH AF: 0.0398

GnomAD4 exome AF: 0.0533 AC: 20208 AN: 379380 Hom.: 674 AF XY: 0.0550 AC XY: 10879 AN XY: 197974

African (AFR) AF: 0.00830 AC: 92 AN: 11090

American (AMR) AF: 0.0433 AC: 755 AN: 17436

Ashkenazi Jewish (ASJ) AF: 0.0169 AC: 200 AN: 11844

East Asian (EAS) AF: 0.0905 AC: 2698 AN: 29822

South Asian (SAS) AF: 0.0904 AC: 2381 AN: 26342

European-Finnish (FIN) AF: 0.0583 AC: 2320 AN: 39824

Middle Eastern (MID) AF: 0.0263 AC: 43 AN: 1634

European-Non Finnish (NFE) AF: 0.0485 AC: 10679 AN: 220024

Other (OTH) AF: 0.0487 AC: 1040 AN: 21364

GnomAD4 genome AF: 0.0421 AC: 6401 AN: 152214 Hom.: 168 Cov.: 32 AF XY: 0.0439 AC XY: 3265 AN XY: 74426

African (AFR) AF: 0.00855 AC: 355 AN: 41536

American (AMR) AF: 0.0408 AC: 624 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0187 AC: 65 AN: 3468

East Asian (EAS) AF: 0.118 AC: 611 AN: 5184

South Asian (SAS) AF: 0.107 AC: 516 AN: 4818

European-Finnish (FIN) AF: 0.0591 AC: 626 AN: 10594

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.0511 AC: 3475 AN: 68006

Other (OTH) AF: 0.0403 AC: 85 AN: 2110

Alfa AF: 0.0501 Hom.: 44

Bravo AF: 0.0390

Asia WGS AF: 0.0910 AC: 315 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 26, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.56
DANN	Benign	0.19
PhyloP100		-0.11
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs74363042; hg19: chr15-40898788;