rs76098847

chr15-40625195-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.4931A>G(p.Lys1644Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00274 in 1,613,938 control chromosomes in the GnomAD database, including 109 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.014 (49 hom., cov: 32)
  • Exomes 𝑓: 0.0016 (60 hom.)
• Consequence: KNL1 NM_144508.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.683

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=0.002418071).
• BP6: Variant 15-40625195-A-G is Benign according to our data. Variant chr15-40625195-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 128603.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0505 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KNL1	NM_144508.5	c.4931A>G	p.Lys1644Arg	missense_variant	10/26	ENST00000399668.7
KNL1	NM_170589.5	c.5009A>G	p.Lys1670Arg	missense_variant	11/27

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KNL1	ENST00000399668.7	c.4931A>G	p.Lys1644Arg	missense_variant	10/26	1	NM_144508.5	A2

Frequencies

GnomAD3 genomes AF: 0.0136 AC: 2068 AN: 152156 Hom.: 48 Cov.: 32

Gnomad AFR AF: 0.0470

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00524

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000323

Gnomad OTH AF: 0.00814

GnomAD3 exomes AF: 0.00343 AC: 855 AN: 249156 Hom.: 26 AF XY: 0.00273 AC XY: 369 AN XY: 135192

Gnomad AFR exome AF: 0.0476

Gnomad AMR exome AF: 0.00221

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000274

Gnomad OTH exome AF: 0.00116

GnomAD4 exome AF: 0.00160 AC: 2341 AN: 1461664 Hom.: 60 Cov.: 34 AF XY: 0.00145 AC XY: 1053 AN XY: 727142

Gnomad4 AFR exome AF: 0.0525

Gnomad4 AMR exome AF: 0.00244

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000139

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000192

Gnomad4 OTH exome AF: 0.00381

GnomAD4 genome AF: 0.0137 AC: 2084 AN: 152274 Hom.: 49 Cov.: 32 AF XY: 0.0132 AC XY: 985 AN XY: 74466

Gnomad4 AFR AF: 0.0472

Gnomad4 AMR AF: 0.00523

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000323

Gnomad4 OTH AF: 0.00806

Alfa AF: 0.00238 Hom.: 13

Bravo AF: 0.0162

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.0436 AC: 159

ESP6500EA AF: 0.000122 AC: 1

ExAC AF: 0.00422 AC: 510

Asia WGS AF: 0.00404 AC: 14 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000356

ClinVar

Significance: Benign/Likely 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	Invitae	Dec 31, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 04, 2020	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Apr 16, 2013

- -

Primary Microcephaly, Recessive Benign:1

Likely 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	0.087
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.65
Cadd	Benign	21
Dann	Uncertain	1.0
DEOGEN2	Benign	0.12	T;T;.
Eigen	Benign	-0.20
Eigen_PC	Benign	-0.11
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.65	T;T;T
MetaRNN	Benign	0.0024	T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-1.7	N;.;N
REVEL	Benign	0.036
Sift	Benign	0.058	T;.;T
Sift4G	Benign	0.20	T;T;T
Polyphen		0.36	B;.;B
Vest4		0.075
MVP		0.37
MPC		0.050
ClinPred		0.010	T
GERP RS		4.4
Varity_R		0.10
gMVP		0.24

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: rs76098847; hg19: chr15-40917393;