rs11858113

chr15-40621979-T-C

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.1715T>C(p.Met572Thr) 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 1,613,456 control chromosomes in the GnomAD database, including 128,915 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 0.39 (11805 hom., cov: 32)
  • Exomes 𝑓: 0.40 (117110 hom.)
• Consequence: KNL1 NM_144508.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.52

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0021754205).
• BP6: Variant 15-40621979-T-C is Benign according to our data. Variant chr15-40621979-T-C is described in ClinVar as [Benign]. Clinvar id is 128589.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.444 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KNL1	NM_144508.5	c.1715T>C	p.Met572Thr	missense_variant	10/26	ENST00000399668.7
KNL1	NM_170589.5	c.1793T>C	p.Met598Thr	missense_variant	11/27

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KNL1	ENST00000399668.7	c.1715T>C	p.Met572Thr	missense_variant	10/26	1	NM_144508.5	A2

Frequencies

GnomAD3 genomes AF: 0.391 AC: 59385 AN: 151990 Hom.: 11787 Cov.: 32

Gnomad AFR AF: 0.373

Gnomad AMI AF: 0.394

Gnomad AMR AF: 0.328

Gnomad ASJ AF: 0.405

Gnomad EAS AF: 0.246

Gnomad SAS AF: 0.460

Gnomad FIN AF: 0.469

Gnomad MID AF: 0.481

Gnomad NFE AF: 0.409

Gnomad OTH AF: 0.370

GnomAD3 exomes AF: 0.386 AC: 96131 AN: 248854 Hom.: 19533 AF XY: 0.399 AC XY: 53865 AN XY: 135030

Gnomad AFR exome AF: 0.369

Gnomad AMR exome AF: 0.258

Gnomad ASJ exome AF: 0.417

Gnomad EAS exome AF: 0.239

Gnomad SAS exome AF: 0.484

Gnomad FIN exome AF: 0.461

Gnomad NFE exome AF: 0.407

Gnomad OTH exome AF: 0.397

GnomAD4 exome AF: 0.397 AC: 579650 AN: 1461348 Hom.: 117110 Cov.: 48 AF XY: 0.401 AC XY: 291601 AN XY: 726978

Gnomad4 AFR exome AF: 0.373

Gnomad4 AMR exome AF: 0.267

Gnomad4 ASJ exome AF: 0.410

Gnomad4 EAS exome AF: 0.250

Gnomad4 SAS exome AF: 0.493

Gnomad4 FIN exome AF: 0.458

Gnomad4 NFE exome AF: 0.397

Gnomad4 OTH exome AF: 0.400

GnomAD4 genome AF: 0.391 AC: 59439 AN: 152108 Hom.: 11805 Cov.: 32 AF XY: 0.393 AC XY: 29216 AN XY: 74354

Gnomad4 AFR AF: 0.373

Gnomad4 AMR AF: 0.328

Gnomad4 ASJ AF: 0.405

Gnomad4 EAS AF: 0.246

Gnomad4 SAS AF: 0.460

Gnomad4 FIN AF: 0.469

Gnomad4 NFE AF: 0.409

Gnomad4 OTH AF: 0.374

Alfa AF: 0.399 Hom.: 30313

Bravo AF: 0.374

TwinsUK AF: 0.399 AC: 1480

ALSPAC AF: 0.400 AC: 1541

ESP6500AA AF: 0.368 AC: 1375

ESP6500EA AF: 0.402 AC: 3307

ExAC AF: 0.392 AC: 47340

Asia WGS AF: 0.374 AC: 1302 AN: 3478

EpiCase AF: 0.401

EpiControl AF: 0.398

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Apr 25, 2013

- -

Primary Microcephaly, Recessive Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Microcephaly 4, primary, autosomal recessive Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 20, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.62
Cadd	Benign	12
Dann	Benign	0.88
DEOGEN2	Benign	0.32	T;T;.
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.47
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.38	T;T;T
MetaRNN	Benign	0.0022	T;T;T
MetaSVM	Benign	-0.94	T
MutationTaster	Benign	0.97	P;P;P
PrimateAI	Benign	0.28	T
PROVEAN	Uncertain	-2.9	D;.;D
REVEL	Benign	0.13
Sift	Benign	0.20	T;.;T
Sift4G	Uncertain	0.0080	D;D;D
Polyphen		0.88	P;.;B
Vest4		0.33
MPC		0.041
ClinPred		0.025	T
GERP RS		0.77
Varity_R		0.14
gMVP		0.41

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: rs11858113; hg19: chr15-40914177; COSMIC: COSV61151299; COSMIC: COSV61151299;