rs201311057

Variant names:

• chr15-40605155-A-G
• rs201311057
• NM_144508.5:c.75+6A>G

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Moderate BP6 BS1 BS2

The NM_144508.5(KNL1):​c.75+6A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000957 in 1,441,882 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00080 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00098 (2 hom.)
• Consequence: KNL1 NM_144508.5 splice_region, intron
• Scores: Splicing: ADA: 0.0009230
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 0.840

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

Our verdict: Benign. The variant received -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.44).
• BP6: Variant 15-40605155-A-G is Benign according to our data. Variant chr15-40605155-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 315841.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}. Variant chr15-40605155-A-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000801 (122/152318) while in subpopulation NFE AF = 0.00132 (90/68030). AF 95% confidence interval is 0.0011. There are 0 homozygotes in GnomAd4. There are 47 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KNL1	NM_144508.5	c.75+6A>G		splice_region_variant, intron_variant	Intron 3 of 25	ENST00000399668.7	NP_653091.3
KNL1	NM_170589.5	c.75+6A>G		splice_region_variant, intron_variant	Intron 3 of 26		NP_733468.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KNL1	ENST00000399668.7	c.75+6A>G		splice_region_variant, intron_variant	Intron 3 of 25	1	NM_144508.5	ENSP00000382576.3

Frequencies

GnomAD3 genomes AF: 0.000802 AC: 122 AN: 152200 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000290

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00132

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.000876 AC: 217 AN: 247838 AF XY: 0.000809

Gnomad AFR exome AF: 0.000130

Gnomad AMR exome AF: 0.00121

Gnomad ASJ exome AF: 0.000100

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000701

Gnomad NFE exome AF: 0.00129

Gnomad OTH exome AF: 0.00200

GnomAD4 exome AF: 0.000976 AC: 1258 AN: 1289564 Hom.: 2 Cov.: 19 AF XY: 0.000951 AC XY: 619 AN XY: 650974

African (AFR) AF: 0.000133 AC: 4 AN: 30100

American (AMR) AF: 0.00141 AC: 62 AN: 44084

Ashkenazi Jewish (ASJ) AF: 0.000439 AC: 11 AN: 25054

East Asian (EAS) AF: 0.00 AC: 0 AN: 38866

South Asian (SAS) AF: 0.00 AC: 0 AN: 82562

European-Finnish (FIN) AF: 0.000603 AC: 32 AN: 53066

Middle Eastern (MID) AF: 0.000739 AC: 4 AN: 5416

European-Non Finnish (NFE) AF: 0.00116 AC: 1105 AN: 955832

Other (OTH) AF: 0.000733 AC: 40 AN: 54584

GnomAD4 genome AF: 0.000801 AC: 122 AN: 152318 Hom.: 0 Cov.: 32 AF XY: 0.000631 AC XY: 47 AN XY: 74480

African (AFR) AF: 0.000289 AC: 12 AN: 41570

American (AMR) AF: 0.000654 AC: 10 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.000471 AC: 5 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00132 AC: 90 AN: 68030

Other (OTH) AF: 0.00189 AC: 4 AN: 2114

Alfa AF: 0.00102 Hom.: 0

Bravo AF: 0.000790

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:2

Aug 05, 2019

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

KNL1: BP4, BS2 -

Microcephaly 4, primary, autosomal recessive Uncertain:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.44
CADD	Benign	18
DANN	Benign	0.80
Mutation Taster		=93/7	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00092
dbscSNV1_RF	Benign	0.064
SpliceAI score (max)		0.040		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: rs201311057; hg19: chr15-40897353;