Variant 17-46067549-G-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_015443.4(KANSL1):c.1652C>G(p.Thr551Ser) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000215 in 1,395,552 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

KANSL1
NM_015443.4 missense, splice_region

Scores

Splicing: ADA: 0.0001996

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.16

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.063688934).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KANSL1	NM_015443.4 link	c.1652C>G	p.Thr551Ser	missense_variant, splice_region_variant	5/15	ENST00000432791.7	NP_056258.1	Q7Z3B3-1A0A024R9Y2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KANSL1	ENST00000432791.7 link	c.1652C>G	p.Thr551Ser	missense_variant, splice_region_variant	5/15	1	NM_015443.4	ENSP00000387393.3		Q7Z3B3-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000215

AC:

AN:

1395552

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

698098

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000190

Gnomad4 OTH exome

AF:

0.0000172

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Koolen-de Vries syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 23, 2023

This sequence change replaces threonine, which is neutral and polar, with serine, which is neutral and polar, at codon 551 of the KANSL1 protein (p.Thr551Ser). 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 output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The serine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. ClinVar contains an entry for this variant (Variation ID: 1416108). This variant has not been reported in the literature in individuals affected with KANSL1-related conditions. This variant is not present in population databases (gnomAD no frequency). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.066

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.66

CADD

Benign

DANN

Benign

0.65

Eigen

Benign

-0.46

Eigen_PC

Benign

-0.26

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.57

.;.;.;.;T;T;T;T;T;T

M_CAP

Benign

0.0081

MetaRNN

Benign

0.064

T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-1.1

PrimateAI

Benign

0.36

PROVEAN

Benign

0.59

N;.;.;.;.;N;.;.;.;.

REVEL

Benign

0.029

Sift

Benign

0.75

T;.;.;.;.;T;.;.;.;.

Sift4G

Benign

1.0

T;T;T;.;T;T;.;.;.;.

Vest4

0.13

MutPred

0.26

Gain of disorder (P = 0.0438);Gain of disorder (P = 0.0438);Gain of disorder (P = 0.0438);Gain of disorder (P = 0.0438);Gain of disorder (P = 0.0438);Gain of disorder (P = 0.0438);Gain of disorder (P = 0.0438);Gain of disorder (P = 0.0438);.;Gain of disorder (P = 0.0438);

MVP

0.082

MPC

0.41

ClinPred

0.044

GERP RS

3.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

gMVP

0.28

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00020

dbscSNV1_RF

Benign

0.29

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over