rs141726041

chr15-40624434-T-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_144508.5(KNL1):c.4170T>A(p.Asp1390Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00119 in 1,613,996 control chromosomes in the GnomAD database, including 10 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 0.0016 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (9 hom.)
• Consequence: KNL1 NM_144508.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.0670

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=0.002544582).
• BP6: Variant 15-40624434-T-A is Benign according to our data. Variant chr15-40624434-T-A is described in ClinVar as [Likely_benign]. Clinvar id is 128599.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-40624434-T-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00162 (247/152328) while in subpopulation EAS AF= 0.0218 (113/5190). AF 95% confidence interval is 0.0185. There are 1 homozygotes in gnomad4. There are 126 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KNL1	NM_144508.5	c.4170T>A	p.Asp1390Glu	missense_variant	10/26	ENST00000399668.7
KNL1	NM_170589.5	c.4248T>A	p.Asp1416Glu	missense_variant	11/27

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KNL1	ENST00000399668.7	c.4170T>A	p.Asp1390Glu	missense_variant	10/26	1	NM_144508.5	A2

Frequencies

GnomAD3 genomes AF: 0.00166 AC: 252 AN: 152210 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00615

Gnomad ASJ AF: 0.00260

Gnomad EAS AF: 0.0223

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000338

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.00382 AC: 953 AN: 249218 Hom.: 8 AF XY: 0.00304 AC XY: 411 AN XY: 135228

Gnomad AFR exome AF: 0.0000646

Gnomad AMR exome AF: 0.0126

Gnomad ASJ exome AF: 0.00397

Gnomad EAS exome AF: 0.0226

Gnomad SAS exome AF: 0.000360

Gnomad FIN exome AF: 0.000326

Gnomad NFE exome AF: 0.000389

Gnomad OTH exome AF: 0.00165

GnomAD4 exome AF: 0.00114 AC: 1673 AN: 1461668 Hom.: 9 Cov.: 34 AF XY: 0.00105 AC XY: 764 AN XY: 727126

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0114

Gnomad4 ASJ exome AF: 0.00321

Gnomad4 EAS exome AF: 0.0175

Gnomad4 SAS exome AF: 0.000475

Gnomad4 FIN exome AF: 0.000431

Gnomad4 NFE exome AF: 0.000213

Gnomad4 OTH exome AF: 0.00141

GnomAD4 genome AF: 0.00162 AC: 247 AN: 152328 Hom.: 1 Cov.: 32 AF XY: 0.00169 AC XY: 126 AN XY: 74498

Gnomad4 AFR AF: 0.0000240

Gnomad4 AMR AF: 0.00615

Gnomad4 ASJ AF: 0.00260

Gnomad4 EAS AF: 0.0218

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.000282

Gnomad4 NFE AF: 0.000338

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.00110 Hom.: 0

Bravo AF: 0.00252

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000610 AC: 5

ExAC AF: 0.00337 AC: 407

Asia WGS AF: 0.00404 AC: 14 AN: 3478

EpiCase AF: 0.000709

EpiControl AF: 0.000296

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 29, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 31, 2019	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jan 06, 2016

- -

Microcephaly 4, primary, autosomal recessive Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.60
Cadd	Benign	15
Dann	Uncertain	1.0
DEOGEN2	Benign	0.14	T;T;.
Eigen	Benign	0.084
Eigen_PC	Benign	0.041
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.63	T;T;T
MetaRNN	Benign	0.0025	T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-2.0	N;.;N
REVEL	Benign	0.068
Sift	Pathogenic	0.0	D;.;D
Sift4G	Uncertain	0.022	D;D;D
Polyphen		0.88	P;.;P
Vest4		0.056
MutPred		0.31		Gain of methylation at K1419 (P = 0.0728);.;.;
MVP		0.45
MPC		0.045
ClinPred		0.048	T
GERP RS		4.0
Varity_R		0.30
gMVP		0.074

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: rs141726041; hg19: chr15-40916632;