15-40625535-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6 BP7 BS1

The NM_144508.5(KNL1):c.5271C>T(p.Cys1757=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000426 in 1,607,592 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0022 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00024 (2 hom.)
• Consequence: KNL1 NM_144508.5 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: -0.167

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 15-40625535-C-T is Benign according to our data. Variant chr15-40625535-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 210571.We mark this variant Likely_benign, oryginal submissions are: {Benign=2, Likely_benign=2, Uncertain_significance=1}. Variant chr15-40625535-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.167 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00223 (339/151940) while in subpopulation AFR AF= 0.0077 (319/41428). AF 95% confidence interval is 0.007. There are 0 homozygotes in gnomad4. There are 178 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KNL1	NM_144508.5	c.5271C>T	p.Cys1757=	synonymous_variant	10/26	ENST00000399668.7
KNL1	NM_170589.5	c.5349C>T	p.Cys1783=	synonymous_variant	11/27

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KNL1	ENST00000399668.7	c.5271C>T	p.Cys1757=	synonymous_variant	10/26	1	NM_144508.5	A2

Frequencies

GnomAD3 genomes AF: 0.00221 AC: 336 AN: 151822 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00765

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000525

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000736

Gnomad OTH AF: 0.00336

GnomAD3 exomes AF: 0.000638 AC: 155 AN: 242774 Hom.: 1 AF XY: 0.000561 AC XY: 74 AN XY: 132006

Gnomad AFR exome AF: 0.00850

Gnomad AMR exome AF: 0.000459

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000540

Gnomad OTH exome AF: 0.000681

GnomAD4 exome AF: 0.000238 AC: 346 AN: 1455652 Hom.: 2 Cov.: 33 AF XY: 0.000224 AC XY: 162 AN XY: 724198

Gnomad4 AFR exome AF: 0.00693

Gnomad4 AMR exome AF: 0.000585

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000353

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000423

Gnomad4 OTH exome AF: 0.000566

GnomAD4 genome AF: 0.00223 AC: 339 AN: 151940 Hom.: 0 Cov.: 32 AF XY: 0.00240 AC XY: 178 AN XY: 74272

Gnomad4 AFR AF: 0.00770

Gnomad4 AMR AF: 0.000524

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000736

Gnomad4 OTH AF: 0.00332

Alfa AF: 0.000398 Hom.: 1

Bravo AF: 0.00237

EpiCase AF: 0.000327

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jan 28, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 24, 2017	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 12, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 31, 2019	- -

Microcephaly 4, primary, autosomal recessive Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
Cadd	Benign	0.20
Dann	Benign	0.18

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: rs191249840; hg19: chr15-40917733;