rs12148454

Variant names:

• chr15-40594355-G-A
• rs12148454
• ENST00000533001.1:n.91G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_144508.5(KNL1):​c.-55G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.064 in 152,346 control chromosomes in the GnomAD database, including 424 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.064 (424 hom., cov: 33)
  • Exomes 𝑓: 0.093 (0 hom.)
• Consequence: KNL1 NM_144508.5 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.199
• Publications: 6 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.64).
• BP6: Variant 15-40594355-G-A is Benign according to our data. Variant chr15-40594355-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 315839.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0835 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KNL1	NM_144508.5	c.-55G>A		5_prime_UTR_variant	Exon 1 of 26	ENST00000399668.7	NP_653091.3
KNL1	NM_170589.5	c.-55G>A		5_prime_UTR_variant	Exon 1 of 27		NP_733468.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KNL1	ENST00000399668.7	c.-55G>A		5_prime_UTR_variant	Exon 1 of 26	1	NM_144508.5	ENSP00000382576.3

Frequencies

GnomAD3 genomes AF: 0.0640 AC: 9739 AN: 152174 Hom.: 424 Cov.: 33

Gnomad AFR AF: 0.0165

Gnomad AMI AF: 0.0691

Gnomad AMR AF: 0.0689

Gnomad ASJ AF: 0.107

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.0377

Gnomad FIN AF: 0.133

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.0853

Gnomad OTH AF: 0.0721

GnomAD4 exome AF: 0.0926 AC: 5 AN: 54 Hom.: 0 Cov.: 0 AF XY: 0.0909 AC XY: 4 AN XY: 44

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 2

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.109 AC: 5 AN: 46

Other (OTH) AF: 0.00 AC: 0 AN: 4

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.019125), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0639 AC: 9738 AN: 152292 Hom.: 424 Cov.: 33 AF XY: 0.0655 AC XY: 4882 AN XY: 74482

African (AFR) AF: 0.0165 AC: 685 AN: 41592

American (AMR) AF: 0.0688 AC: 1052 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.107 AC: 370 AN: 3468

East Asian (EAS) AF: 0.000578 AC: 3 AN: 5190

South Asian (SAS) AF: 0.0379 AC: 183 AN: 4830

European-Finnish (FIN) AF: 0.133 AC: 1408 AN: 10608

Middle Eastern (MID) AF: 0.0680 AC: 20 AN: 294

European-Non Finnish (NFE) AF: 0.0853 AC: 5802 AN: 67984

Other (OTH) AF: 0.0718 AC: 152 AN: 2116

Alfa AF: 0.0786 Hom.: 602

Bravo AF: 0.0577

Asia WGS AF: 0.0210 AC: 72 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Primary Microcephaly, Recessive Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
CADD	Benign	8.7
DANN	Benign	0.88
PhyloP100		0.20
PromoterAI		0.025	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=299/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs12148454; hg19: chr15-40886553;