rs767021119

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM1BP4_StrongBS1_SupportingBS2

The NM_015443.4(KANSL1):​c.802T>C​(p.Ser268Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000378 in 1,613,986 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 35)
Exomes 𝑓: 0.000040 ( 0 hom. )

Consequence

KANSL1
NM_015443.4 missense

Scores

1
16

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.543
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

PM1
In a modified_residue Phosphoserine (size 0) in uniprot entity KANL1_HUMAN
BP4
Computational evidence support a benign effect (MetaRNN=0.029243767).
BS1
Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.0000131 (2/152100) while in subpopulation EAS AF= 0.000386 (2/5184). AF 95% confidence interval is 0.0000683. There are 0 homozygotes in gnomad4. There are 2 alleles in male gnomad4 subpopulation. Median coverage is 35. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
BS2
High AC in GnomAdExome4 at 59 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
KANSL1NM_015443.4 linkc.802T>C p.Ser268Pro missense_variant Exon 2 of 15 ENST00000432791.7 NP_056258.1 Q7Z3B3-1A0A024R9Y2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
KANSL1ENST00000432791.7 linkc.802T>C p.Ser268Pro missense_variant Exon 2 of 15 1 NM_015443.4 ENSP00000387393.3 Q7Z3B3-1

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152100
Hom.:
0
Cov.:
35
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:
0.000386
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
GnomAD3 exomes
AF:
0.000103
AC:
26
AN:
251436
Hom.:
0
AF XY:
0.000103
AC XY:
14
AN XY:
135896
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000289
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000652
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000967
Gnomad OTH exome
AF:
0.000326
GnomAD4 exome
AF:
0.0000404
AC:
59
AN:
1461886
Hom.:
0
Cov.:
33
AF XY:
0.0000316
AC XY:
23
AN XY:
727242
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.000680
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.0000374
Gnomad4 NFE exome
AF:
0.0000207
Gnomad4 OTH exome
AF:
0.0000828
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152100
Hom.:
0
Cov.:
35
AF XY:
0.0000269
AC XY:
2
AN XY:
74284
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000386
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000529
ExAC
AF:
0.000165
AC:
20

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Koolen-de Vries syndrome Uncertain:1
Sep 17, 2021
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.070
BayesDel_addAF
Benign
-0.52
T
BayesDel_noAF
Benign
-0.62
CADD
Benign
14
DANN
Benign
0.97
Eigen
Benign
-0.45
Eigen_PC
Benign
-0.24
FATHMM_MKL
Uncertain
0.78
D
LIST_S2
Benign
0.67
.;.;.;.;T;T;T;T;T
M_CAP
Benign
0.0057
T
MetaRNN
Benign
0.029
T;T;T;T;T;T;T;T;T
MetaSVM
Benign
-0.99
T
PrimateAI
Benign
0.39
T
PROVEAN
Benign
-0.46
N;.;.;.;.;N;.;.;.
REVEL
Benign
0.022
Sift
Benign
0.35
T;.;.;.;.;T;.;.;.
Sift4G
Benign
0.29
T;T;T;.;T;T;.;.;.
Vest4
0.16
MutPred
0.29
Gain of catalytic residue at S268 (P = 9e-04);Gain of catalytic residue at S268 (P = 9e-04);Gain of catalytic residue at S268 (P = 9e-04);Gain of catalytic residue at S268 (P = 9e-04);Gain of catalytic residue at S268 (P = 9e-04);Gain of catalytic residue at S268 (P = 9e-04);Gain of catalytic residue at S268 (P = 9e-04);Gain of catalytic residue at S268 (P = 9e-04);Gain of catalytic residue at S268 (P = 9e-04);
MVP
0.043
MPC
0.018
ClinPred
0.014
T
GERP RS
3.6
gMVP
0.11

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs767021119; hg19: chr17-44248708; API