rs144882998

Positions:

• chr17-46171524-T-A
• chr17-46171524-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4 BP6

The NM_015443.4(KANSL1):​c.620A>T​(p.Asn207Ile) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N207S) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 35)
• Consequence: KANSL1 NM_015443.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 3.92

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]

KANSL1 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.26454115).
• BP6: Variant 17-46171524-T-A is Benign according to our data. Variant chr17-46171524-T-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 386241.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KANSL1	NM_015443.4	c.620A>T	p.Asn207Ile	missense_variant	2/15	ENST00000432791.7	NP_056258.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KANSL1	ENST00000432791.7	c.620A>T	p.Asn207Ile	missense_variant	2/15	1	NM_015443.4	ENSP00000387393.3

Frequencies

GnomAD3 genomes Cov.: 35

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 35

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Koolen-de Vries syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Mar 28, 2019

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C15"). This variant has not been reported in the literature in individuals with KANSL1-related conditions. ClinVar contains an entry for this variant (Variation ID: 386241). This variant is not present in population databases (ExAC no frequency). This sequence change replaces asparagine with isoleucine at codon 207 of the KANSL1 protein (p.Asn207Ile). The asparagine residue is highly conserved and there is a large physicochemical difference between asparagine and isoleucine. -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

May 18, 2016

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.39
BayesDel_addAF	Benign	-0.013	T
BayesDel_noAF	Benign	-0.26
CADD	Uncertain	25
DANN	Uncertain	0.99
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.93	.;.;.;.;D;D;D;D;D
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.26	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
PrimateAI	Uncertain	0.49	T
PROVEAN	Uncertain	-2.4	N;.;.;.;.;N;.;.;.
REVEL	Benign	0.18
Sift	Uncertain	0.0030	D;.;.;.;.;D;.;.;.
Sift4G	Uncertain	0.031	D;D;D;.;D;D;.;.;.
Vest4		0.71
MutPred		0.35		Gain of sheet (P = 0.0049);Gain of sheet (P = 0.0049);Gain of sheet (P = 0.0049);Gain of sheet (P = 0.0049);Gain of sheet (P = 0.0049);Gain of sheet (P = 0.0049);Gain of sheet (P = 0.0049);Gain of sheet (P = 0.0049);Gain of sheet (P = 0.0049);
MVP		0.15
MPC		0.10
ClinPred		0.60	D
GERP RS		6.0
gMVP		0.28

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: rs144882998; hg19: chr17-44248890;