rs774841964

Positions:

• chr17-46066611-G-A
• chr17-46066611-G-C
• chr17-46066611-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3 PP5

The NM_015443.4(KANSL1):​c.1774C>T​(p.Arg592Trp) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: KANSL1 NM_015443.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:2
• Conservation: PhyloP100: 4.04

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.832
• PP5: Variant 17-46066611-G-A is Pathogenic according to our data. Variant chr17-46066611-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 468399.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=3, Pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KANSL1	NM_015443.4	c.1774C>T	p.Arg592Trp	missense_variant	6/15	ENST00000432791.7	NP_056258.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KANSL1	ENST00000432791.7	c.1774C>T	p.Arg592Trp	missense_variant	6/15	1	NM_015443.4	ENSP00000387393	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratoire Génétique Moléculaire, CHRU TOURS	Apr 06, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 30, 2023	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Missense variant in a gene in which most reported pathogenic variants are truncating/loss-of-function; This variant is associated with the following publications: (PMID: 36150256, 31273778) -

Koolen-de Vries syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 01, 2017	This variant has been shown to arise de novo in individuals affected with a seizure disorder (Invitae). However, previously reported disease-causing de novo variants in KANSL1 have been truncations or gene deletions (PMID: 2544363, 26424144, 22544367, 26306646). In summary, this variant has been observed to arise de novo in a single individual. In the absence of additional clinical or functional data, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with tryptophan at codon 592 of the KANSL1 protein (p.Arg592Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Feb 19, 2020	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
CADD	Pathogenic	29
DANN	Pathogenic	1.0
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Pathogenic	0.98	.;.;.;.;D;D;D;D;D;D
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.83	D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	-0.25	T
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-7.4	D;.;.;.;.;D;.;.;.;.
REVEL	Pathogenic	0.65
Sift	Pathogenic	0.0	D;.;.;.;.;D;.;.;.;.
Sift4G	Pathogenic	0.0010	D;D;D;.;D;D;.;.;.;.
Vest4		0.98
MutPred		0.66		Loss of disorder (P = 0.0075);Loss of disorder (P = 0.0075);Loss of disorder (P = 0.0075);Loss of disorder (P = 0.0075);Loss of disorder (P = 0.0075);Loss of disorder (P = 0.0075);Loss of disorder (P = 0.0075);Loss of disorder (P = 0.0075);.;Loss of disorder (P = 0.0075);
MVP		0.80
MPC		1.4
ClinPred		1.0	D
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.70

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: rs774841964; hg19: chr17-44143977; COSMIC: COSV52267096;