rs12911738

Variant names:

• chr15-40611486-A-G
• rs12911738
• NM_144508.5:c.259A>G

Your query was ambiguous. Multiple possible variants found:

• chr15-40611486-A-G
• chr15-40611486-A-T

Variant summary

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

The ENST00000399668.7(KNL1):​c.259A>G​(p.Thr87Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.801 in 229,010 control chromosomes in the GnomAD database, including 75,673 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.83 (53115 hom., cov: 32)
  • Exomes 𝑓: 0.75 (22558 hom.)
• Consequence: KNL1 ENST00000399668.7 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.755
• Publications: 33 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=1.0240715E-6).
• BP6: Variant 15-40611486-A-G is Benign according to our data. Variant chr15-40611486-A-G is described in ClinVar as Benign. ClinVar VariationId is 128595.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.906 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000399668.7. 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.259A>G	p.Thr87Ala	missense	Exon 7 of 26	NP_653091.3
	KNL1	NM_170589.5		c.337A>G	p.Thr113Ala	missense	Exon 8 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.259A>G	p.Thr87Ala	missense	Exon 7 of 26	ENSP00000382576.3
	KNL1	ENST00000346991.9	TSL:1	c.337A>G	p.Thr113Ala	missense	Exon 8 of 27	ENSP00000335463.6
	KNL1	ENST00000533001.1	TSL:1	n.404A>G		non_coding_transcript_exon	Exon 7 of 10

Frequencies

GnomAD3 genomes AF: 0.826 AC: 125524 AN: 151954 Hom.: 53068 Cov.: 32

Gnomad AFR AF: 0.914

Gnomad AMI AF: 0.763

Gnomad AMR AF: 0.673

Gnomad ASJ AF: 0.806

Gnomad EAS AF: 0.324

Gnomad SAS AF: 0.727

Gnomad FIN AF: 0.846

Gnomad MID AF: 0.854

Gnomad NFE AF: 0.852

Gnomad OTH AF: 0.807

GnomAD2 exomes AF: 0.785 AC: 26011 AN: 33116 AF XY: 0.773

Gnomad AFR exome AF: 0.899

Gnomad AMR exome AF: 0.511

Gnomad ASJ exome AF: 0.743

Gnomad EAS exome AF: 0.320

Gnomad FIN exome AF: 0.844

Gnomad NFE exome AF: 0.809

Gnomad OTH exome AF: 0.745

GnomAD4 exome AF: 0.751 AC: 57811 AN: 76938 Hom.: 22558 Cov.: 0 AF XY: 0.747 AC XY: 28683 AN XY: 38372

African (AFR) AF: 0.827 AC: 708 AN: 856

American (AMR) AF: 0.374 AC: 353 AN: 944

Ashkenazi Jewish (ASJ) AF: 0.690 AC: 1143 AN: 1656

East Asian (EAS) AF: 0.119 AC: 103 AN: 864

South Asian (SAS) AF: 0.648 AC: 3183 AN: 4914

European-Finnish (FIN) AF: 0.843 AC: 13609 AN: 16140

Middle Eastern (MID) AF: 0.749 AC: 433 AN: 578

European-Non Finnish (NFE) AF: 0.754 AC: 36707 AN: 48698

Other (OTH) AF: 0.687 AC: 1572 AN: 2288

GnomAD4 genome AF: 0.826 AC: 125619 AN: 152072 Hom.: 53115 Cov.: 32 AF XY: 0.819 AC XY: 60873 AN XY: 74348

African (AFR) AF: 0.914 AC: 37927 AN: 41502

American (AMR) AF: 0.672 AC: 10271 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.806 AC: 2799 AN: 3472

East Asian (EAS) AF: 0.323 AC: 1673 AN: 5178

South Asian (SAS) AF: 0.727 AC: 3506 AN: 4824

European-Finnish (FIN) AF: 0.846 AC: 8911 AN: 10532

Middle Eastern (MID) AF: 0.844 AC: 248 AN: 294

European-Non Finnish (NFE) AF: 0.852 AC: 57888 AN: 67976

Other (OTH) AF: 0.806 AC: 1700 AN: 2108

Alfa AF: 0.843 Hom.: 77803

Bravo AF: 0.808

TwinsUK AF: 0.850 AC: 3150

ALSPAC AF: 0.845 AC: 3257

ExAC AF: 0.756 AC: 14833

Asia WGS AF: 0.556 AC: 1932 AN: 3470

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	Microcephaly 4, primary, autosomal recessive (1)
-	-	1	Primary Microcephaly, Recessive (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	4.9
DANN	Benign	0.85
DEOGEN2	Benign	0.014	T
Eigen	Benign	-0.97
Eigen_PC	Benign	-0.77
FATHMM_MKL	Benign	0.0035	N
LIST_S2	Benign	0.15	T
MetaRNN	Benign	0.0000010	T
MetaSVM	Benign	-0.99	T
PhyloP100		0.76
PrimateAI	Benign	0.35	T
PROVEAN	Benign	0.77	N
REVEL	Benign	0.075
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.045
MPC		0.037
ClinPred		0.00063	T
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.037
gMVP		0.050
Mutation Taster		=84/16	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs12911738; hg19: chr15-40903684; COSMIC: COSV61154720; COSMIC: COSV61154720;