rs551541795

chr17-46171334-CAG-C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 9P and 4B. PVS1 PP5 BS2

The NM_015443.4(KANSL1):c.808_809del(p.Leu270ValfsTer11) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000161 in 1,614,018 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. L270L) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 35)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: KANSL1 NM_015443.4 frameshift
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:6 U:2
• Conservation: PhyloP100: 2.03

Genes affected

KANSL1 (HGNC:24565): (KAT8 regulatory NSL complex subunit 1) This gene encodes a nuclear protein that is a subunit of two protein complexes involved with histone acetylation, the MLL1 complex and the NSL1 complex. The encoded protein has been implicated in a variety of cellular processes including enhancer regulation, cell proliferation, and mitosis. Mutations in this gene are associated with Koolen-de Vries Syndrome. [provided by RefSeq, May 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 17-46171334-CAG-C is Pathogenic according to our data. Variant chr17-46171334-CAG-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 468412.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=4, Likely_pathogenic=2, Uncertain_significance=2}. Variant chr17-46171334-CAG-C is described in Lovd as [Likely_pathogenic].
• BS2: High AC in GnomAdExome at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KANSL1	NM_015443.4	c.808_809del	p.Leu270ValfsTer11	frameshift_variant	2/15	ENST00000432791.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KANSL1	ENST00000432791.7	c.808_809del	p.Leu270ValfsTer11	frameshift_variant	2/15	1	NM_015443.4	P4

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152140 Hom.: 0 Cov.: 35

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000239 AC: 6 AN: 251458 Hom.: 0 AF XY: 0.0000368 AC XY: 5 AN XY: 135898

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000164 AC: 24 AN: 1461878 Hom.: 0 AF XY: 0.0000206 AC XY: 15 AN XY: 727244

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000153

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152140 Hom.: 0 Cov.: 35 AF XY: 0.0000135 AC XY: 1 AN XY: 74322

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000843 Hom.: 0

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:6 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Koolen-de Vries syndrome Pathogenic:3 Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 28, 2018	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	May 26, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Breda Genetics srl	Jun 23, 2022	The variant c.808_809del (p.Leu270Valfs*11) in the KANSL1 gene is reported with conflicting interpretations (pathogenic, likely pathogenic, uncertain) in ClinVar for Koolen-de Vries syndrome (Variation ID: 168412) and as likely pathogenic in the LOVD database v.3.0 (genomic variant: #0000795640). The variant c.808_809del (p.Leu270Valfs*11) has been reported as pathogenic by Niar et al. (2018, PMID: 30293248) in a patient with a diagnosis of Koolen-deVries syndrome, which had developmental delay, intellectual disability, hypotony, ptosis, short stature, and ligamentous laxity. The variant creates a shift in the reading frame which is predicted to result in a premature stop codon 11 amino acids downstream, which is likely to result in a truncated protein or protein loss due to nonsense-mediated messenger decay (NMD). The variant is reported with an estimated allele frequency of 0.00002386 in gnomAD exomes and di 0.00003185 in gnomAD genomes with no homozygous individuals reported. -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Aug 31, 2021	- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 28, 2023

The c.808_809delCT (p.L270Vfs*11) alteration, located in exon 2 (coding exon 1) of the KANSL1 gene, consists of a deletion of 2 nucleotides from position 808 to 809, causing a translational frameshift with a predicted alternate stop codon after 11 amino acids. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on data from gnomAD, the c.808_809delCT allele has an overall frequency of 0.002% (7/282852) total alleles studied. The highest observed frequency was 0.01% (3/30616) of South Asian alleles. Loss of function alterations in this region of the KANSL1 gene are more common in population databases than expected for likely pathogenic/disease-causing variants (Koolen, 2015). Based on the available evidence, this alteration is classified as pathogenic. -

KANSL1-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 25, 2023

The KANSL1 c.808_809delCT variant is predicted to result in a frameshift and premature protein termination (p.Leu270Valfs*11). This variant was reported in multiple individuals with Koolen-de Vries syndrome or a neurodevelopmental phenotype. In many cases, the variant arose de novo (Nair et al. 2018. PubMed ID: 30293248; Table S1 - Gabriel et al. 2021. PubMed ID: 34958143; Tolusso et al. 2021. PubMed ID: 33442022; Table S2 - Turner et al. 2019. PubMed ID: 31785789). This variant is reported in 0.0098% of alleles in individuals of South Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/17-44248700-CAG-C). Frameshift variants in KANSL1 are expected to be pathogenic. This variant is interpreted as pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Apr 01, 2019

- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Mendelics

May 04, 2022

- -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs551541795; hg19: chr17-44248700;