dbSNP rs145938212: KANSL1:p.Ala634Ser (chr17-46050653-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_015443.4(KANSL1):c.1900G>T(p.Ala634Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,614,014 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A634T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

KANSL1
NM_015443.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.80

Publications

3 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: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.21116796).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KANSL1	NM_015443.4 link	c.1900G>T	p.Ala634Ser	missense_variant	Exon 7 of 15	ENST00000432791.7	NP_056258.1	Q7Z3B3-1A0A024R9Y2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KANSL1	ENST00000432791.7 link	c.1900G>T	p.Ala634Ser	missense_variant	Exon 7 of 15	1	NM_015443.4	ENSP00000387393.3		Q7Z3B3-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152156

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461858

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727234

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111990

Other (OTH)

AF:

0.00

AC:

AN:

60394

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

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:

0.00000657

AC:

AN:

152156

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74326

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41430

American (AMR)

AF:

0.00

AC:

AN:

15260

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5198

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68028

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

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

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Benign

-0.51

CADD

Benign

(source)

DANN

Uncertain

0.99

Eigen

Benign

-0.039

Eigen_PC

Benign

-0.048

FATHMM_MKL

Uncertain

0.80

LIST_S2

Uncertain

0.96

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

M_CAP

Benign

0.012

MetaRNN

Benign

0.21

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

MetaSVM

Benign

-1.1

PhyloP100

2.8

PrimateAI

Benign

0.35

PROVEAN

Benign

-1.6

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

REVEL

Benign

0.050

Sift

Benign

0.094

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

Sift4G

Benign

0.26

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

Vest4

0.54

MutPred

0.34

Gain of disorder (P = 0.0106);Gain of disorder (P = 0.0106);Gain of disorder (P = 0.0106);Gain of disorder (P = 0.0106);Gain of disorder (P = 0.0106);Gain of disorder (P = 0.0106);Gain of disorder (P = 0.0106);Gain of disorder (P = 0.0106);.;Gain of disorder (P = 0.0106);

MVP

0.25

MPC

0.58

ClinPred

0.75

GERP RS

5.1

PromoterAI

-0.027

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

gMVP

0.30

Mutation Taster

=92/8

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over