rs555296963

chr15-40611471-T-A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 2P and 7B. PM2 BP4_Moderate BP6 BS1

The NM_144508.5(KNL1):c.251-7T>A variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000879 in 235,482 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.0010 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00064 (0 hom.)
• Consequence: KNL1 NM_144508.5 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.3797
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 1.88

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 Likely_benign. Variant got -5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.31).
• BP6: Variant 15-40611471-T-A is Benign according to our data. Variant chr15-40611471-T-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 210566.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=1}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00101 (154/152276) while in subpopulation NFE AF= 0.00185 (126/68016). AF 95% confidence interval is 0.00159. There are 0 homozygotes in gnomad4. There are 58 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KNL1	NM_144508.5	c.251-7T>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000399668.7
KNL1	NM_170589.5	c.329-7T>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KNL1	ENST00000399668.7	c.251-7T>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_144508.5	A2

Frequencies

GnomAD3 genomes AF: 0.00101 AC: 154 AN: 152158 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000265

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

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: 0.00185

Gnomad OTH AF: 0.00383

GnomAD3 exomes AF: 0.000479 AC: 15 AN: 31306 Hom.: 0 AF XY: 0.000438 AC XY: 7 AN XY: 15998

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000191

Gnomad NFE exome AF: 0.000998

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000637 AC: 53 AN: 83206 Hom.: 0 Cov.: 0 AF XY: 0.000609 AC XY: 25 AN XY: 41058

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000248

Gnomad4 NFE exome AF: 0.000891

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00101 AC: 154 AN: 152276 Hom.: 0 Cov.: 31 AF XY: 0.000779 AC XY: 58 AN XY: 74474

Gnomad4 AFR AF: 0.000265

Gnomad4 AMR AF: 0.000588

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00185

Gnomad4 OTH AF: 0.00379

Alfa AF: 0.00125 Hom.: 0

Bravo AF: 0.000990

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Dec 04, 2014

- -

Primary Microcephaly, Recessive Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.31
Cadd	Benign	16
Dann	Benign	0.87

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.38
dbscSNV1_RF	Benign	0.35
SpliceAI score (max)		0.16		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: rs555296963; hg19: chr15-40903669;