Genetic Variant KANSL1:p.Phe860Phe (chr17-46034247-A-G) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_015443.4(KANSL1):c.2580T>C(p.Phe860Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.189 in 1,613,590 control chromosomes in the GnomAD database, including 32,776 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.14 ( 2136 hom., cov: 32)

Exomes 𝑓: 0.19 ( 30640 hom. )

Consequence

KANSL1
NM_015443.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -0.635

Publications

47 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.82).

BP6

Variant 17-46034247-A-G is Benign according to our data. Variant chr17-46034247-A-G is described in ClinVar as Benign. ClinVar VariationId is 323767.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.635 with no splicing effect.

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.2580T>C	p.Phe860Phe	synonymous	Exon 11 of 15	NP_056258.1
KANSL1	NM_001193466.2		c.2580T>C	p.Phe860Phe	synonymous	Exon 11 of 15	NP_001180395.1
KANSL1	NM_001379198.1		c.2580T>C	p.Phe860Phe	synonymous	Exon 12 of 16	NP_001366127.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
KANSL1	ENST00000432791.7	TSL:1 MANE Select	c.2580T>C	p.Phe860Phe	synonymous	Exon 11 of 15	ENSP00000387393.3
KANSL1	ENST00000262419.10	TSL:1	c.2580T>C	p.Phe860Phe	synonymous	Exon 11 of 15	ENSP00000262419.6
KANSL1	ENST00000572218.5	TSL:1	n.6797T>C		non_coding_transcript_exon	Exon 4 of 8

Frequencies

GnomAD3 genomes

AF:

0.143

AC:

21812

AN:

152136

Hom.:

2138

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0429

Gnomad AMI

AF:

0.278

Gnomad AMR

AF:

0.176

Gnomad ASJ

AF:

0.240

Gnomad EAS

AF:

0.00154

Gnomad SAS

AF:

0.0736

Gnomad FIN

AF:

0.0649

Gnomad MID

AF:

0.218

Gnomad NFE

AF:

0.217

Gnomad OTH

AF:

0.184

GnomAD2 exomes

AF:

0.145

AC:

36448

AN:

251234

AF XY:

0.149

show subpopulations

Gnomad AFR exome

AF:

0.0398

Gnomad AMR exome

AF:

0.119

Gnomad ASJ exome

AF:

0.254

Gnomad EAS exome

AF:

0.000652

Gnomad FIN exome

AF:

0.0681

Gnomad NFE exome

AF:

0.213

Gnomad OTH exome

AF:

0.175

GnomAD4 exome

AF:

0.193

AC:

282555

AN:

1461336

Hom.:

30640

Cov.:

AF XY:

0.191

AC XY:

138803

AN XY:

726990

show subpopulations

African (AFR)

AF:

0.0365

AC:

1221

AN:

33474

American (AMR)

AF:

0.125

AC:

5597

AN:

44686

Ashkenazi Jewish (ASJ)

AF:

0.256

AC:

6694

AN:

26124

East Asian (EAS)

AF:

0.000882

AC:

AN:

39688

South Asian (SAS)

AF:

0.0795

AC:

6854

AN:

86224

European-Finnish (FIN)

AF:

0.0724

AC:

3867

AN:

53416

Middle Eastern (MID)

AF:

0.202

AC:

1163

AN:

5768

European-Non Finnish (NFE)

AF:

0.222

AC:

246452

AN:

1111584

Other (OTH)

AF:

0.177

AC:

10672

AN:

60372

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

11282

22564

33845

45127

56409

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

8220

16440

24660

32880

41100

<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:

21801

AN:

152254

Hom.:

2136

Cov.:

AF XY:

0.134

AC XY:

9973

AN XY:

74430

show subpopulations

African (AFR)

AF:

0.0428

AC:

1780

AN:

41550

American (AMR)

AF:

0.175

AC:

2682

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.240

AC:

834

AN:

3470

East Asian (EAS)

AF:

0.00154

AC:

AN:

5188

South Asian (SAS)

AF:

0.0736

AC:

355

AN:

4822

European-Finnish (FIN)

AF:

0.0649

AC:

689

AN:

10616

Middle Eastern (MID)

AF:

0.214

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.217

AC:

14754

AN:

68000

Other (OTH)

AF:

0.181

AC:

383

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

917

1833

2750

3666

4583

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:

0.198

Hom.:

4833

Bravo

AF:

0.148

Asia WGS

AF:

0.0310

AC:

109

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

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

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Apr 20, 2017

Athena Diagnostics

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

BayesDel_noAF

Benign

-0.82

CADD

Benign

1.6

(source)

DANN

Benign

0.54

PhyloP100

-0.64

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

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