17-46171417-G-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBP6_Very_Strong

The NM_015443.4(KANSL1):c.727C>A(p.Gln243Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00226 in 1,612,980 control chromosomes in the GnomAD database, including 1 homozygotes. There is a variant allele frequency bias in the population database for this variant (GnomAd4), which may indicate mosaicism or somatic mutations in the reference population data. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. Q243Q) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0017 ( 0 hom., cov: 35)

Exomes 𝑓: 0.0023 ( 1 hom. )

Consequence

KANSL1
NM_015443.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 2.40

Publications

6 publications found

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 Gene-Disease associations (from GenCC):

Koolen-de Vries syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), ClinGen
Koolen-de Vries syndrome due to a point mutation
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

KANSL1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.005876094).

BP6

Variant 17-46171417-G-T is Benign according to our data. Variant chr17-46171417-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 205776.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KANSL1	NM_015443.4 link	c.727C>A	p.Gln243Lys	missense_variant	Exon 2 of 15	ENST00000432791.7	NP_056258.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KANSL1	ENST00000432791.7 link	c.727C>A	p.Gln243Lys	missense_variant	Exon 2 of 15	1	NM_015443.4	ENSP00000387393.3

Frequencies

GnomAD3 genomes

AF:

0.00167

AC:

254

AN:

152110

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000410

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00157

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00340

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00249

Gnomad OTH

AF:

0.00191

GnomAD2 exomes

AF:

0.00188

AC:

471

AN:

251178

AF XY:

0.00187

show subpopulations

Gnomad AFR exome

AF:

0.000246

Gnomad AMR exome

AF:

0.00130

Gnomad ASJ exome

AF:

0.00238

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00269

Gnomad NFE exome

AF:

0.00283

Gnomad OTH exome

AF:

0.00261

GnomAD4 exome

AF:

0.00233

AC:

3398

AN:

1460752

Hom.:

Cov.:

AF XY:

0.00229

AC XY:

1662

AN XY:

726716

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.000299

AC:

AN:

33478

American (AMR)

AF:

0.00132

AC:

AN:

44708

Ashkenazi Jewish (ASJ)

AF:

0.00214

AC:

AN:

26122

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000812

AC:

AN:

86244

European-Finnish (FIN)

AF:

0.00230

AC:

123

AN:

53396

Middle Eastern (MID)

AF:

0.00139

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00270

AC:

3005

AN:

1110964

Other (OTH)

AF:

0.00214

AC:

129

AN:

60372

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.293

Heterozygous variant carriers

240

480

719

959

1199

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

196

294

392

490

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00167

AC:

254

AN:

152228

Hom.:

Cov.:

AF XY:

0.00153

AC XY:

114

AN XY:

74420

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.000409

AC:

AN:

41546

American (AMR)

AF:

0.00157

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00115

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00340

AC:

AN:

10598

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00249

AC:

169

AN:

67996

Other (OTH)

AF:

0.00189

AC:

AN:

2112

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.333

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00266

Hom.:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00244

AC:

ExAC

AF:

0.00181

AC:

220

EpiCase

AF:

0.00382

EpiControl

AF:

0.00415

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

May 03, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Missense variant in a gene in which most reported pathogenic variants are truncating/loss-of-function; In silico analysis supports that this missense variant does not alter protein structure/function; Located in a region that tolerates variation and lacks pathogenic variants -

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

KANSL1: BP4 -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jun 29, 2018

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not specified

Benign:1

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Inborn genetic diseases

Benign:1

Mar 29, 2022

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Koolen-de Vries syndrome

Benign:1

Oct 25, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.092

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.42

CADD

Benign

(source)

DANN

Benign

0.96

Eigen

Benign

-0.12

Eigen_PC

Benign

0.12

FATHMM_MKL

Uncertain

0.85

LIST_S2

Benign

0.85

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

M_CAP

Benign

0.0044

MetaRNN

Benign

0.0059

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

MetaSVM

Benign

-0.98

PhyloP100

2.4

PrimateAI

Benign

0.36

PROVEAN

Benign

-1.2

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

REVEL

Benign

0.088

Sift

Benign

0.039

D;.;.;.;.;D;.;.;.

Sift4G

Benign

0.66

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

Vest4

0.31

MVP

0.11

MPC

0.021

ClinPred

0.0093

GERP RS

6.0

PromoterAI

-0.018

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

gMVP

0.22

Mutation Taster

=91/9

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over