rs12907984

Variant names:

• chr15-40605388-G-A
• rs12907984
• NM_144508.5:c.75+239G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_144508.5(KNL1):​c.75+239G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.254 in 152,060 control chromosomes in the GnomAD database, including 6,011 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.25 (6011 hom., cov: 32)
• Consequence: KNL1 NM_144508.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.07
• Publications: 7 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=-0.88).
• BP6: Variant 15-40605388-G-A is Benign according to our data. Variant chr15-40605388-G-A is described in ClinVar as [Benign]. Clinvar id is 1255333.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.335 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KNL1	NM_144508.5	c.75+239G>A		intron_variant	Intron 3 of 25	ENST00000399668.7	NP_653091.3
KNL1	NM_170589.5	c.75+239G>A		intron_variant	Intron 3 of 26		NP_733468.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KNL1	ENST00000399668.7	c.75+239G>A		intron_variant	Intron 3 of 25	1	NM_144508.5	ENSP00000382576.3

Frequencies

GnomAD3 genomes AF: 0.254 AC: 38559 AN: 151942 Hom.: 6006 Cov.: 32

Gnomad AFR AF: 0.0772

Gnomad AMI AF: 0.322

Gnomad AMR AF: 0.250

Gnomad ASJ AF: 0.365

Gnomad EAS AF: 0.102

Gnomad SAS AF: 0.345

Gnomad FIN AF: 0.392

Gnomad MID AF: 0.367

Gnomad NFE AF: 0.339

Gnomad OTH AF: 0.256

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.254 AC: 38563 AN: 152060 Hom.: 6011 Cov.: 32 AF XY: 0.258 AC XY: 19212 AN XY: 74334

African (AFR) AF: 0.0770 AC: 3197 AN: 41520

American (AMR) AF: 0.250 AC: 3810 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.365 AC: 1267 AN: 3468

East Asian (EAS) AF: 0.102 AC: 531 AN: 5184

South Asian (SAS) AF: 0.344 AC: 1659 AN: 4816

European-Finnish (FIN) AF: 0.392 AC: 4137 AN: 10550

Middle Eastern (MID) AF: 0.367 AC: 108 AN: 294

European-Non Finnish (NFE) AF: 0.339 AC: 23013 AN: 67944

Other (OTH) AF: 0.260 AC: 549 AN: 2108

Alfa AF: 0.305 Hom.: 972

Bravo AF: 0.229

Asia WGS AF: 0.244 AC: 848 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jul 17, 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	-0.88
CADD	Benign	4.9
DANN	Benign	0.57
PhyloP100		1.1
Mutation Taster		=100/0	polymorphism (auto)

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: rs12907984; hg19: chr15-40897586;