chr15-40605207-A-G

Variant names:

• chr15-40605207-A-G
• rs74985610
• NM_144508.5:c.75+58A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_144508.5(KNL1):​c.75+58A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00164 in 971,040 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0065 (12 hom., cov: 32)
  • Exomes 𝑓: 0.00074 (10 hom.)
• Consequence: KNL1 NM_144508.5 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.749
• Publications: 1 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=-0.92).
• BP6: Variant 15-40605207-A-G is Benign according to our data. Variant chr15-40605207-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 1189472.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00651 (991/152318) while in subpopulation AFR AF = 0.0227 (943/41580). AF 95% confidence interval is 0.0215. There are 12 homozygotes in GnomAd4. There are 467 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 12 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KNL1	NM_144508.5	c.75+58A>G		intron_variant	Intron 3 of 25	ENST00000399668.7	NP_653091.3
KNL1	NM_170589.5	c.75+58A>G		intron_variant	Intron 3 of 26		NP_733468.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KNL1	ENST00000399668.7	c.75+58A>G		intron_variant	Intron 3 of 25	1	NM_144508.5	ENSP00000382576.3

Frequencies

GnomAD3 genomes AF: 0.00639 AC: 973 AN: 152200 Hom.: 12 Cov.: 32

Gnomad AFR AF: 0.0223

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00216

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00528

GnomAD4 exome AF: 0.000740 AC: 606 AN: 818722 Hom.: 10 AF XY: 0.000606 AC XY: 262 AN XY: 432450

African (AFR) AF: 0.0228 AC: 473 AN: 20716

American (AMR) AF: 0.000923 AC: 38 AN: 41172

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21586

East Asian (EAS) AF: 0.00 AC: 0 AN: 36704

South Asian (SAS) AF: 0.0000280 AC: 2 AN: 71400

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51372

Middle Eastern (MID) AF: 0.00155 AC: 7 AN: 4522

European-Non Finnish (NFE) AF: 0.0000639 AC: 34 AN: 532296

Other (OTH) AF: 0.00133 AC: 52 AN: 38954

GnomAD4 genome AF: 0.00651 AC: 991 AN: 152318 Hom.: 12 Cov.: 32 AF XY: 0.00627 AC XY: 467 AN XY: 74486

African (AFR) AF: 0.0227 AC: 943 AN: 41580

American (AMR) AF: 0.00216 AC: 33 AN: 15298

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68026

Other (OTH) AF: 0.00522 AC: 11 AN: 2106

Alfa AF: 0.00538 Hom.: 2

Bravo AF: 0.00723

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Feb 07, 2019

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	-0.92
CADD	Benign	0.16
DANN	Benign	0.45
PhyloP100		-0.75
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: rs74985610; hg19: chr15-40897405;