15-40605388-G-A

Position:

• chr15-40605388-G-A

Variant summary

Our verdict is Benign. Variant got -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

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -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/exons	MANE	Protein	UniProt
KNL1	NM_144508.5	c.75+239G>A		intron_variant		ENST00000399668.7	NP_653091.3
KNL1	NM_170589.5	c.75+239G>A		intron_variant			NP_733468.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KNL1	ENST00000399668.7	c.75+239G>A		intron_variant		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

Gnomad4 AFR AF: 0.0770

Gnomad4 AMR AF: 0.250

Gnomad4 ASJ AF: 0.365

Gnomad4 EAS AF: 0.102

Gnomad4 SAS AF: 0.344

Gnomad4 FIN AF: 0.392

Gnomad4 NFE AF: 0.339

Gnomad4 OTH AF: 0.260

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

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 17, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	4.9
DANN	Benign	0.57

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

LitVar

Other links and lift over

dbSNP: rs12907984; hg19: chr15-40897586;