Genetic Variant KANSL1:p.His167Arg (chr17-46171644-T-C) – ACMG Classification: Benign (-11 pts)

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_ModerateBP6BS1BS2

The NM_015443.4(KANSL1):c.500A>G(p.His167Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000116 in 1,557,192 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict 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. H167P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 35)

Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

KANSL1
NM_015443.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: 2.07

Publications

0 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 -11 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.07711652).

BP6

Variant 17-46171644-T-C is Benign according to our data. Variant chr17-46171644-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 205768.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0000131 (2/152322) while in subpopulation AMR AF = 0.000131 (2/15304). AF 95% confidence interval is 0.0000226. There are 0 homozygotes in GnomAd4. There are 0 alleles in the male GnomAd4 subpopulation. Median coverage is 35. This position passed quality control check.

BS2

High AC in GnomAdExome4 at 16 AD gene.

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.500A>G	p.His167Arg	missense	Exon 2 of 15	NP_056258.1
KANSL1	NM_001193466.2		c.500A>G	p.His167Arg	missense	Exon 2 of 15	NP_001180395.1
KANSL1	NM_001379198.1		c.500A>G	p.His167Arg	missense	Exon 3 of 16	NP_001366127.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
KANSL1	ENST00000432791.7	TSL:1 MANE Select	c.500A>G	p.His167Arg	missense	Exon 2 of 15	ENSP00000387393.3
KANSL1	ENST00000262419.10	TSL:1	c.500A>G	p.His167Arg	missense	Exon 2 of 15	ENSP00000262419.6
KANSL1	ENST00000572904.6	TSL:5	c.500A>G	p.His167Arg	missense	Exon 2 of 15	ENSP00000461484.1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152204

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000596

AC:

AN:

201436

AF XY:

0.0000556

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000411

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000104

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000114

AC:

AN:

1404870

Hom.:

Cov.:

AF XY:

0.0000101

AC XY:

AN XY:

694916

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30970

American (AMR)

AF:

0.000330

AC:

AN:

33326

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22106

East Asian (EAS)

AF:

0.0000255

AC:

AN:

39256

South Asian (SAS)

AF:

0.0000129

AC:

AN:

77234

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50450

Middle Eastern (MID)

AF:

0.000184

AC:

AN:

5446

European-Non Finnish (NFE)

AF:

9.19e-7

AC:

AN:

1088236

Other (OTH)

AF:

0.0000173

AC:

AN:

57846

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152322

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74474

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41554

American (AMR)

AF:

0.000131

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68042

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

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:

0.0000267

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.0000495

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Koolen-de Vries syndrome

Uncertain:1

Jul 13, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Due to the possible presence of a polymorphic segmental duplication, the location of the variant could not be unambiguously resolved. Variants with ambiguous mapping are still reported relative to the KANSL1 transcript. This sequence change replaces histidine with arginine at codon 167 of the KANSL1 protein (p.His167Arg). The histidine residue is highly conserved and there is a small physicochemical difference between histidine and arginine. The frequency data for this variant in the population databases (ExAC) is considered unreliable due to the presence of homologous sequence, such as pseudogenes or paralogs, in the genome. This variant has not been reported in the literature in individuals with KANSL1-related conditions. ClinVar contains an entry for this variant (Variation ID: 205768). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. Until the location of this sequence change can be resolved, the clinical significance of this variant remains uncertain. It has been classified as a Variant of Uncertain Significance.

Inborn genetic diseases

Benign:1

Oct 29, 2021

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.

not provided

Benign:1

Mar 28, 2019

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.43

CADD

Benign

(source)

DANN

Benign

0.94

Eigen

Benign

-0.23

Eigen_PC

Benign

0.014

FATHMM_MKL

Uncertain

0.86

LIST_S2

Benign

0.78

M_CAP

Benign

0.0046

MetaRNN

Benign

0.077

MetaSVM

Benign

-0.93

PhyloP100

2.1

PrimateAI

Uncertain

0.56

PROVEAN

Benign

-1.4

REVEL

Benign

0.15

Sift

Benign

0.42

Sift4G

Benign

0.37

Vest4

0.41

MutPred

0.20

Gain of MoRF binding (P = 0.0029)

MVP

0.27

MPC

0.023

ClinPred

0.033

GERP RS

5.0

PromoterAI

0.00040

Neutral

(source)

gMVP

0.095

Mutation Taster

=95/5

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

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