17-46031540-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_015443.4(KANSL1):c.3254T>C(p.Ile1085Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.189 in 1,613,758 control chromosomes in the GnomAD database, including 32,754 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.14 ( 2129 hom., cov: 32)

Exomes 𝑓: 0.19 ( 30625 hom. )

Consequence

KANSL1
NM_015443.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.905

Publications

41 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0036968887).

BP6

Variant 17-46031540-A-G is Benign according to our data. Variant chr17-46031540-A-G is described in ClinVar as Benign. ClinVar VariationId is 323762.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.214 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015443.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
KANSL1	NM_015443.4	MANE Select	c.3254T>C	p.Ile1085Thr	missense	Exon 15 of 15	NP_056258.1
KANSL1	NM_001193466.2		c.3254T>C	p.Ile1085Thr	missense	Exon 15 of 15	NP_001180395.1
KANSL1	NM_001379198.1		c.3254T>C	p.Ile1085Thr	missense	Exon 16 of 16	NP_001366127.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
KANSL1	ENST00000432791.7	TSL:1 MANE Select	c.3254T>C	p.Ile1085Thr	missense	Exon 15 of 15	ENSP00000387393.3
KANSL1	ENST00000262419.10	TSL:1	c.3254T>C	p.Ile1085Thr	missense	Exon 15 of 15	ENSP00000262419.6
KANSL1	ENST00000572218.5	TSL:1	n.7471T>C		non_coding_transcript_exon	Exon 8 of 8

Frequencies

GnomAD3 genomes

AF:

0.143

AC:

21803

AN:

152076

Hom.:

2131

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0430

Gnomad AMI

AF:

0.277

Gnomad AMR

AF:

0.176

Gnomad ASJ

AF:

0.240

Gnomad EAS

AF:

0.00155

Gnomad SAS

AF:

0.0733

Gnomad FIN

AF:

0.0651

Gnomad MID

AF:

0.218

Gnomad NFE

AF:

0.217

Gnomad OTH

AF:

0.184

GnomAD2 exomes

AF:

0.144

AC:

36044

AN:

249624

AF XY:

0.148

show subpopulations

Gnomad AFR exome

AF:

0.0397

Gnomad AMR exome

AF:

0.118

Gnomad ASJ exome

AF:

0.254

Gnomad EAS exome

AF:

0.000654

Gnomad FIN exome

AF:

0.0674

Gnomad NFE exome

AF:

0.212

Gnomad OTH exome

AF:

0.175

GnomAD4 exome

AF:

0.193

AC:

282680

AN:

1461564

Hom.:

30625

Cov.:

AF XY:

0.191

AC XY:

138830

AN XY:

727042

show subpopulations

African (AFR)

AF:

0.0365

AC:

1223

AN:

33480

American (AMR)

AF:

0.125

AC:

5593

AN:

44700

Ashkenazi Jewish (ASJ)

AF:

0.256

AC:

6698

AN:

26128

East Asian (EAS)

AF:

0.000882

AC:

AN:

39700

South Asian (SAS)

AF:

0.0795

AC:

6856

AN:

86240

European-Finnish (FIN)

AF:

0.0723

AC:

3856

AN:

53350

Middle Eastern (MID)

AF:

0.201

AC:

1161

AN:

5762

European-Non Finnish (NFE)

AF:

0.222

AC:

246583

AN:

1111846

Other (OTH)

AF:

0.177

AC:

10675

AN:

60358

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

13923

27846

41770

55693

69616

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

8232

16464

24696

32928

41160

<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:

0.143

AC:

21792

AN:

152194

Hom.:

2129

Cov.:

AF XY:

0.134

AC XY:

9972

AN XY:

74408

show subpopulations

African (AFR)

AF:

0.0429

AC:

1783

AN:

41548

American (AMR)

AF:

0.176

AC:

2683

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.240

AC:

834

AN:

3472

East Asian (EAS)

AF:

0.00155

AC:

AN:

5160

South Asian (SAS)

AF:

0.0734

AC:

353

AN:

4812

European-Finnish (FIN)

AF:

0.0651

AC:

691

AN:

10618

Middle Eastern (MID)

AF:

0.214

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.217

AC:

14741

AN:

67986

Other (OTH)

AF:

0.181

AC:

383

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

948

1896

2843

3791

4739

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

236

472

708

944

1180

<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:

0.199

Hom.:

8077

Bravo

AF:

0.148

TwinsUK

AF:

0.233

AC:

865

ALSPAC

AF:

0.242

AC:

931

ESP6500AA

AF:

0.0461

AC:

203

ESP6500EA

AF:

0.223

AC:

1914

ExAC

AF:

0.143

AC:

17393

Asia WGS

AF:

0.0310

AC:

109

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 23222517)

Apr 20, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

MAPT-Related Spectrum Disorders

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Koolen-de Vries syndrome

Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.064

BayesDel_addAF

Benign

-0.82

BayesDel_noAF

Benign

-0.81

CADD

Benign

3.2

(source)

DANN

Benign

0.64

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.33

LIST_S2

Benign

0.045

MetaRNN

Benign

0.0037

MetaSVM

Benign

-0.97

PhyloP100

0.91

PrimateAI

Benign

0.32

PROVEAN

Benign

0.25

REVEL

Benign

0.032

Sift

Benign

0.40

Sift4G

Uncertain

0.020

Vest4

0.0060

MPC

0.58

ClinPred

0.00062

GERP RS

2.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

gMVP

0.043

Mutation Taster

=99/1

polymorphism (auto)

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over