15-40652039-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM2 PP5_Moderate BP4

The NM_144508.5(KNL1):c.6349G>T(p.Asp2117Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: KNL1 NM_144508.5 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 2.04

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 15-40652039-G-T is Pathogenic according to our data. Variant chr15-40652039-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 495234.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.39303225).. Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KNL1	NM_144508.5	c.6349G>T	p.Asp2117Tyr	missense_variant	21/26	ENST00000399668.7
KNL1	NM_170589.5	c.6427G>T	p.Asp2143Tyr	missense_variant	22/27

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KNL1	ENST00000399668.7	c.6349G>T	p.Asp2117Tyr	missense_variant	21/26	1	NM_144508.5	A2
KNL1	ENST00000346991.9	c.6427G>T	p.Asp2143Tyr	missense_variant	22/27	1		P4
KNL1	ENST00000526913.5	c.3484G>T	p.Asp1162Tyr	missense_variant, NMD_transcript_variant	12/18	1
KNL1	ENST00000532347.1	n.429G>T		non_coding_transcript_exon_variant	4/5	4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1461408 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 727024

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: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Microcephaly 4, primary, autosomal recessive Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

NeuroMeGen, Hospital Clinico Santiago de Compostela

Jan 01, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Benign	0.24	T;.
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.72	T;T
M_CAP	Benign	0.0077	T
MetaRNN	Benign	0.39	T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.94	N;N
PrimateAI	Benign	0.44	T
PROVEAN	Pathogenic	-4.4	D;D
REVEL	Benign	0.17
Sift	Benign	0.040	D;D
Sift4G	Uncertain	0.022	D;D
Polyphen		0.99	D;D
Vest4		0.45
MutPred		0.44		Loss of solvent accessibility (P = 0.0193);.;
MVP		0.65
MPC		0.26
ClinPred		0.98	D
GERP RS		3.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.21
gMVP		0.40

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: rs758157294; hg19: chr15-40944237;