rs12911738

chr15-40611486-A-Gchr15-40611486-A-T

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.259A>G(p.Thr87Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.801 in 229,010 control chromosomes in the GnomAD database, including 75,673 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.83 (53115 hom., cov: 32)
  • Exomes 𝑓: 0.75 (22558 hom.)
• Consequence: KNL1 NM_144508.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.755

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=1.0240715E-6).
• BP6: Variant 15-40611486-A-G is Benign according to our data. Variant chr15-40611486-A-G is described in ClinVar as [Benign]. Clinvar id is 128595.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.906 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KNL1	NM_144508.5	c.259A>G	p.Thr87Ala	missense_variant	7/26	ENST00000399668.7
KNL1	NM_170589.5	c.337A>G	p.Thr113Ala	missense_variant	8/27

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KNL1	ENST00000399668.7	c.259A>G	p.Thr87Ala	missense_variant	7/26	1	NM_144508.5	A2

Frequencies

GnomAD3 genomes AF: 0.826 AC: 125524 AN: 151954 Hom.: 53068 Cov.: 32

Gnomad AFR AF: 0.914

Gnomad AMI AF: 0.763

Gnomad AMR AF: 0.673

Gnomad ASJ AF: 0.806

Gnomad EAS AF: 0.324

Gnomad SAS AF: 0.727

Gnomad FIN AF: 0.846

Gnomad MID AF: 0.854

Gnomad NFE AF: 0.852

Gnomad OTH AF: 0.807

GnomAD3 exomes AF: 0.785 AC: 26011 AN: 33116 Hom.: 10432 AF XY: 0.773 AC XY: 13355 AN XY: 17288

Gnomad AFR exome AF: 0.899

Gnomad AMR exome AF: 0.511

Gnomad ASJ exome AF: 0.743

Gnomad EAS exome AF: 0.320

Gnomad SAS exome AF: 0.635

Gnomad FIN exome AF: 0.844

Gnomad NFE exome AF: 0.809

Gnomad OTH exome AF: 0.745

GnomAD4 exome AF: 0.751 AC: 57811 AN: 76938 Hom.: 22558 Cov.: 0 AF XY: 0.747 AC XY: 28683 AN XY: 38372

Gnomad4 AFR exome AF: 0.827

Gnomad4 AMR exome AF: 0.374

Gnomad4 ASJ exome AF: 0.690

Gnomad4 EAS exome AF: 0.119

Gnomad4 SAS exome AF: 0.648

Gnomad4 FIN exome AF: 0.843

Gnomad4 NFE exome AF: 0.754

Gnomad4 OTH exome AF: 0.687

GnomAD4 genome AF: 0.826 AC: 125619 AN: 152072 Hom.: 53115 Cov.: 32 AF XY: 0.819 AC XY: 60873 AN XY: 74348

Gnomad4 AFR AF: 0.914

Gnomad4 AMR AF: 0.672

Gnomad4 ASJ AF: 0.806

Gnomad4 EAS AF: 0.323

Gnomad4 SAS AF: 0.727

Gnomad4 FIN AF: 0.846

Gnomad4 NFE AF: 0.852

Gnomad4 OTH AF: 0.806

Alfa AF: 0.847 Hom.: 58749

Bravo AF: 0.808

TwinsUK AF: 0.850 AC: 3150

ALSPAC AF: 0.845 AC: 3257

ExAC AF: 0.756 AC: 14833

Asia WGS AF: 0.556 AC: 1932 AN: 3470

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 17, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Mar 24, 2014	- -

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 07, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.64
Cadd	Benign	4.9
Dann	Benign	0.85
DEOGEN2	Benign	0.014	T;T;.
Eigen	Benign	-0.97
Eigen_PC	Benign	-0.77
FATHMM_MKL	Benign	0.0035	N
LIST_S2	Benign	0.15	T;T;T
MetaRNN	Benign	0.0000010	T;T;T
MetaSVM	Benign	-0.99	T
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.35	T
PROVEAN	Benign	0.77	N;.;N
REVEL	Benign	0.075
Sift	Benign	1.0	T;.;T
Sift4G	Benign	1.0	T;T;T
Polyphen		0.0	B;.;B
Vest4		0.045
MPC		0.037
ClinPred		0.00063	T
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.037
gMVP		0.050

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

Publications

LitVar

Other links and lift over

dbSNP: rs12911738; hg19: chr15-40903684; COSMIC: COSV61154720; COSMIC: COSV61154720;