chr15-40611486-A-T

Variant names:

• chr15-40611486-A-T
• rs12911738
• NM_144508.5:c.259A>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_170589.5(KNL1):​c.337A>T​(p.Thr113Ser) 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. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T113A) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: KNL1 NM_170589.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.755
• Publications: 33 publications found

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]

KNL1 Gene-Disease associations (from GenCC):

• microcephaly 4, primary, autosomal recessive

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• autosomal recessive primary microcephaly

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.05035004).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_170589.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KNL1	NM_144508.5	MANE Select	c.259A>T	p.Thr87Ser	missense	Exon 7 of 26	NP_653091.3
	KNL1	NM_170589.5		c.337A>T	p.Thr113Ser	missense	Exon 8 of 27	NP_733468.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KNL1	ENST00000399668.7	TSL:1 MANE Select	c.259A>T	p.Thr87Ser	missense	Exon 7 of 26	ENSP00000382576.3
	KNL1	ENST00000346991.9	TSL:1	c.337A>T	p.Thr113Ser	missense	Exon 8 of 27	ENSP00000335463.6
	KNL1	ENST00000533001.1	TSL:1	n.404A>T		non_coding_transcript_exon	Exon 7 of 10

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 78460 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 39148

African (AFR) AF: 0.00 AC: 0 AN: 884

American (AMR) AF: 0.00 AC: 0 AN: 964

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 1726

East Asian (EAS) AF: 0.00 AC: 0 AN: 874

South Asian (SAS) AF: 0.00 AC: 0 AN: 5042

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 16154

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 582

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 49880

Other (OTH) AF: 0.00 AC: 0 AN: 2354

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 77803

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	10
DANN	Benign	0.90
DEOGEN2	Benign	0.019	T
Eigen	Benign	-0.84
Eigen_PC	Benign	-0.68
FATHMM_MKL	Benign	0.070	N
LIST_S2	Benign	0.18	T
M_CAP	Benign	0.0027	T
MetaRNN	Benign	0.050	T
MetaSVM	Benign	-1.0	T
PhyloP100		0.76
PrimateAI	Benign	0.34	T
PROVEAN	Benign	0.060	N
REVEL	Benign	0.079
Sift	Benign	0.27	T
Sift4G	Benign	0.51	T
Polyphen		0.0	B
Vest4		0.096
MutPred		0.11		Gain of disorder (P = 0.0562)
MVP		0.29
MPC		0.035
ClinPred		0.034	T
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.047
gMVP		0.046

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs12911738; hg19: chr15-40903684;