rs76371152

Variant names:

• chr15-40620991-A-G
• rs76371152
• NM_144508.5:c.727A>G

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.727A>G​(p.Ile243Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00277 in 1,604,072 control chromosomes in the GnomAD database, including 111 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.014 (49 hom., cov: 32)
  • Exomes 𝑓: 0.0016 (62 hom.)
• Consequence: KNL1 NM_144508.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -2.56
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0029896498).
• BP6: Variant 15-40620991-A-G is Benign according to our data. Variant chr15-40620991-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 128607.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0514 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_144508.5. 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.727A>G	p.Ile243Val	missense	Exon 10 of 26	NP_653091.3
	KNL1	NM_170589.5		c.805A>G	p.Ile269Val	missense	Exon 11 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.727A>G	p.Ile243Val	missense	Exon 10 of 26	ENSP00000382576.3
	KNL1	ENST00000346991.9	TSL:1	c.805A>G	p.Ile269Val	missense	Exon 11 of 27	ENSP00000335463.6
	KNL1	ENST00000533001.1	TSL:1	n.872A>G		non_coding_transcript_exon	Exon 10 of 10

Frequencies

GnomAD3 genomes AF: 0.0137 AC: 2086 AN: 152204 Hom.: 48 Cov.: 32

Gnomad AFR AF: 0.0474

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00517

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: 0.00812

GnomAD2 exomes AF: 0.00361 AC: 860 AN: 238454 AF XY: 0.00288

Gnomad AFR exome AF: 0.0488

Gnomad AMR exome AF: 0.00239

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000291

Gnomad OTH exome AF: 0.00141

GnomAD4 exome AF: 0.00161 AC: 2335 AN: 1451750 Hom.: 62 Cov.: 33 AF XY: 0.00146 AC XY: 1056 AN XY: 722256

African (AFR) AF: 0.0535 AC: 1743 AN: 32590

American (AMR) AF: 0.00254 AC: 105 AN: 41292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25554

East Asian (EAS) AF: 0.00 AC: 0 AN: 39624

South Asian (SAS) AF: 0.000177 AC: 15 AN: 84830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53178

Middle Eastern (MID) AF: 0.00335 AC: 19 AN: 5680

European-Non Finnish (NFE) AF: 0.000197 AC: 219 AN: 1109164

Other (OTH) AF: 0.00391 AC: 234 AN: 59838

GnomAD4 genome AF: 0.0138 AC: 2102 AN: 152322 Hom.: 49 Cov.: 32 AF XY: 0.0133 AC XY: 989 AN XY: 74480

African (AFR) AF: 0.0477 AC: 1982 AN: 41562

American (AMR) AF: 0.00516 AC: 79 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

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

European-Non Finnish (NFE) AF: 0.000323 AC: 22 AN: 68032

Other (OTH) AF: 0.00803 AC: 17 AN: 2116

Alfa AF: 0.00489 Hom.: 43

Bravo AF: 0.0164

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.0442 AC: 162

ESP6500EA AF: 0.000122 AC: 1

ExAC AF: 0.00426 AC: 515

Asia WGS AF: 0.00433 AC: 15 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	not specified (1)
-	-	1	Primary Microcephaly, Recessive (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.81	T
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.0010
DANN	Benign	0.29
DEOGEN2	Benign	0.020	T
Eigen	Benign	-2.0
Eigen_PC	Benign	-2.0
FATHMM_MKL	Benign	0.0097	N
LIST_S2	Benign	0.46	T
MetaRNN	Benign	0.0030	T
MetaSVM	Benign	-0.97	T
PhyloP100		-2.6
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-0.040	N
REVEL	Benign	0.017
Sift	Benign	0.86	T
Sift4G	Benign	0.83	T
Polyphen		0.0	B
Vest4		0.031
MVP		0.099
MPC		0.033
ClinPred		0.000026	T
GERP RS		-11
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.018
gMVP		0.053
Mutation Taster		=96/4	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: rs76371152; hg19: chr15-40913189;