NM_144508.5:c.-17-53G>T

Variant names:

• chr15-40602862-G-T
• rs116578977
• NM_144508.5:c.-17-53G>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_144508.5(KNL1):​c.-17-53G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00374 in 958,440 control chromosomes in the GnomAD database, including 94 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.014 (51 hom., cov: 31)
  • Exomes 𝑓: 0.0018 (43 hom.)
• Consequence: KNL1 NM_144508.5 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.74
• Publications: 0 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: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 15-40602862-G-T is Benign according to our data. Variant chr15-40602862-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 1201708.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAdExome4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0509 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KNL1	NM_144508.5	c.-17-53G>T		intron_variant	Intron 1 of 25	ENST00000399668.7	NP_653091.3
KNL1	NM_170589.5	c.-17-53G>T		intron_variant	Intron 1 of 26		NP_733468.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KNL1	ENST00000399668.7	c.-17-53G>T		intron_variant	Intron 1 of 25	1	NM_144508.5	ENSP00000382576.3

Frequencies

GnomAD3 genomes AF: 0.0139 AC: 2115 AN: 152136 Hom.: 49 Cov.: 31

Gnomad AFR AF: 0.0481

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00530

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000323

Gnomad OTH AF: 0.00814

GnomAD4 exome AF: 0.00179 AC: 1445 AN: 806186 Hom.: 43 AF XY: 0.00159 AC XY: 679 AN XY: 425930

African (AFR) AF: 0.0536 AC: 1033 AN: 19272

American (AMR) AF: 0.00266 AC: 93 AN: 34950

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20316

East Asian (EAS) AF: 0.00 AC: 0 AN: 36252

South Asian (SAS) AF: 0.000179 AC: 12 AN: 67098

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47640

Middle Eastern (MID) AF: 0.00389 AC: 17 AN: 4374

European-Non Finnish (NFE) AF: 0.000203 AC: 109 AN: 537892

Other (OTH) AF: 0.00471 AC: 181 AN: 38392

GnomAD4 genome AF: 0.0140 AC: 2137 AN: 152254 Hom.: 51 Cov.: 31 AF XY: 0.0136 AC XY: 1013 AN XY: 74444

African (AFR) AF: 0.0485 AC: 2015 AN: 41532

American (AMR) AF: 0.00529 AC: 81 AN: 15300

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10598

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000323 AC: 22 AN: 68024

Other (OTH) AF: 0.00806 AC: 17 AN: 2110

Alfa AF: 0.00242 Hom.: 0

Bravo AF: 0.0165

Asia WGS AF: 0.00664 AC: 23 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Sep 22, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.060
DANN	Benign	0.40
PhyloP100		-1.7
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs116578977; hg19: chr15-40895060;