NM_144508.5:c.6315-100C>T

Variant names:

• chr15-40651905-C-T
• rs3092980
• NM_144508.5:c.6315-100C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_144508.5(KNL1):​c.6315-100C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0282 in 681,090 control chromosomes in the GnomAD database, including 365 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.024 (60 hom., cov: 32)
  • Exomes 𝑓: 0.029 (305 hom.)
• Consequence: KNL1 NM_144508.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.240
• Publications: 3 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.024 (3657/152230) while in subpopulation NFE AF = 0.0369 (2509/68022). AF 95% confidence interval is 0.0357. There are 60 homozygotes in GnomAd4. There are 1750 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 60 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KNL1	NM_144508.5	c.6315-100C>T		intron_variant	Intron 20 of 25	ENST00000399668.7	NP_653091.3
KNL1	NM_170589.5	c.6393-100C>T		intron_variant	Intron 21 of 26		NP_733468.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KNL1	ENST00000399668.7	c.6315-100C>T		intron_variant	Intron 20 of 25	1	NM_144508.5	ENSP00000382576.3
KNL1	ENST00000346991.9	c.6393-100C>T		intron_variant	Intron 21 of 26	1		ENSP00000335463.6
KNL1	ENST00000526913.5	n.3447-100C>T		intron_variant	Intron 11 of 17	1		ENSP00000432565.1
KNL1	ENST00000532347.1	n.395-100C>T		intron_variant	Intron 3 of 4	4

Frequencies

GnomAD3 genomes AF: 0.0240 AC: 3656 AN: 152114 Hom.: 60 Cov.: 32

Gnomad AFR AF: 0.00609

Gnomad AMI AF: 0.0198

Gnomad AMR AF: 0.0264

Gnomad ASJ AF: 0.0302

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00311

Gnomad FIN AF: 0.0273

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0369

Gnomad OTH AF: 0.0296

GnomAD4 exome AF: 0.0294 AC: 15533 AN: 528860 Hom.: 305 AF XY: 0.0284 AC XY: 7898 AN XY: 278418

African (AFR) AF: 0.00510 AC: 73 AN: 14308

American (AMR) AF: 0.0184 AC: 413 AN: 22410

Ashkenazi Jewish (ASJ) AF: 0.0395 AC: 629 AN: 15936

East Asian (EAS) AF: 0.0000318 AC: 1 AN: 31490

South Asian (SAS) AF: 0.00493 AC: 224 AN: 45414

European-Finnish (FIN) AF: 0.0270 AC: 1047 AN: 38812

Middle Eastern (MID) AF: 0.00364 AC: 13 AN: 3574

European-Non Finnish (NFE) AF: 0.0375 AC: 12321 AN: 328546

Other (OTH) AF: 0.0286 AC: 812 AN: 28370

GnomAD4 genome AF: 0.0240 AC: 3657 AN: 152230 Hom.: 60 Cov.: 32 AF XY: 0.0235 AC XY: 1750 AN XY: 74448

African (AFR) AF: 0.00605 AC: 251 AN: 41514

American (AMR) AF: 0.0264 AC: 403 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0302 AC: 105 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5184

South Asian (SAS) AF: 0.00311 AC: 15 AN: 4820

European-Finnish (FIN) AF: 0.0273 AC: 290 AN: 10608

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0369 AC: 2509 AN: 68022

Other (OTH) AF: 0.0293 AC: 62 AN: 2114

Alfa AF: 0.0299 Hom.: 64

Bravo AF: 0.0239

Asia WGS AF: 0.00289 AC: 10 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	7.4
DANN	Benign	0.74
PhyloP100		-0.24
Mutation Taster		=99/1	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: rs3092980; hg19: chr15-40944103;