chr15-40624039-A-G

Position:

• chr15-40624039-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_144508.5(KNL1):​c.3775A>G​(p.Lys1259Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.396 in 1,613,648 control chromosomes in the GnomAD database, including 136,887 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.31 (9055 hom., cov: 32)
  • Exomes 𝑓: 0.41 (127832 hom.)
• Consequence: KNL1 NM_144508.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.866

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0010717511).
• BP6: Variant 15-40624039-A-G is Benign according to our data. Variant chr15-40624039-A-G is described in ClinVar as [Benign]. Clinvar id is 128598.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-40624039-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.437 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KNL1	NM_144508.5	c.3775A>G	p.Lys1259Glu	missense_variant	10/26	ENST00000399668.7	NP_653091.3
KNL1	NM_170589.5	c.3853A>G	p.Lys1285Glu	missense_variant	11/27		NP_733468.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KNL1	ENST00000399668.7	c.3775A>G	p.Lys1259Glu	missense_variant	10/26	1	NM_144508.5	ENSP00000382576.3

Frequencies

GnomAD3 genomes AF: 0.306 AC: 46528 AN: 151992 Hom.: 9060 Cov.: 32

Gnomad AFR AF: 0.0899

Gnomad AMI AF: 0.370

Gnomad AMR AF: 0.304

Gnomad ASJ AF: 0.401

Gnomad EAS AF: 0.0776

Gnomad SAS AF: 0.263

Gnomad FIN AF: 0.377

Gnomad MID AF: 0.345

Gnomad NFE AF: 0.441

Gnomad OTH AF: 0.339

GnomAD3 exomes AF: 0.329 AC: 81977 AN: 249074 Hom.: 15733 AF XY: 0.337 AC XY: 45495 AN XY: 135168

Gnomad AFR exome AF: 0.0847

Gnomad AMR exome AF: 0.221

Gnomad ASJ exome AF: 0.394

Gnomad EAS exome AF: 0.0835

Gnomad SAS exome AF: 0.269

Gnomad FIN exome AF: 0.382

Gnomad NFE exome AF: 0.432

Gnomad OTH exome AF: 0.378

GnomAD4 exome AF: 0.405 AC: 592418 AN: 1461538 Hom.: 127832 Cov.: 48 AF XY: 0.403 AC XY: 292785 AN XY: 727074

Gnomad4 AFR exome AF: 0.0813

Gnomad4 AMR exome AF: 0.231

Gnomad4 ASJ exome AF: 0.398

Gnomad4 EAS exome AF: 0.0598

Gnomad4 SAS exome AF: 0.267

Gnomad4 FIN exome AF: 0.378

Gnomad4 NFE exome AF: 0.448

Gnomad4 OTH exome AF: 0.376

GnomAD4 genome AF: 0.306 AC: 46511 AN: 152110 Hom.: 9055 Cov.: 32 AF XY: 0.302 AC XY: 22441 AN XY: 74340

Gnomad4 AFR AF: 0.0897

Gnomad4 AMR AF: 0.304

Gnomad4 ASJ AF: 0.401

Gnomad4 EAS AF: 0.0770

Gnomad4 SAS AF: 0.264

Gnomad4 FIN AF: 0.377

Gnomad4 NFE AF: 0.441

Gnomad4 OTH AF: 0.336

Alfa AF: 0.410 Hom.: 21188

Bravo AF: 0.288

TwinsUK AF: 0.450 AC: 1668

ALSPAC AF: 0.443 AC: 1708

ESP6500AA AF: 0.0965 AC: 357

ESP6500EA AF: 0.433 AC: 3546

ExAC AF: 0.327 AC: 39446

Asia WGS AF: 0.145 AC: 504 AN: 3478

EpiCase AF: 0.440

EpiControl AF: 0.442

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 07, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Aug 15, 2013

- -

Primary Microcephaly, Recessive Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	14
DANN	Uncertain	0.99
DEOGEN2	Benign	0.10	T;T;.
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.43
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.59	T;T;T
MetaRNN	Benign	0.0011	T;T;T
MetaSVM	Benign	-0.91	T
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-1.6	N;.;N
REVEL	Benign	0.074
Sift	Benign	0.035	D;.;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		0.99	D;.;D
Vest4		0.12
MPC		0.052
ClinPred		0.0073	T
GERP RS		3.4
Varity_R		0.10
gMVP		0.19

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: rs17747633; hg19: chr15-40916237; COSMIC: COSV61151431; COSMIC: COSV61151431;