rs772236084

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6BS1BS2

The NM_015443.4(KANSL1):​c.889C>T​(p.Arg297Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000164 in 1,461,894 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 35)
Exomes 𝑓: 0.000016 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

KANSL1
NM_015443.4 missense

Scores

8
5
4

Clinical Significance

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

Conservation

PhyloP100: 6.14
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP6
Variant 17-46171255-G-A is Benign according to our data. Variant chr17-46171255-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 517800.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=2}.
BS1
Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.0000164 (24/1461894) while in subpopulation AMR AF= 0.000313 (14/44724). AF 95% confidence interval is 0.000189. There are 0 homozygotes in gnomad4_exome. There are 10 alleles in male gnomad4_exome subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
High AC in GnomAdExome4 at 24 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
KANSL1NM_015443.4 linkc.889C>T p.Arg297Cys 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.889C>T p.Arg297Cys missense_variant Exon 2 of 15 1 NM_015443.4 ENSP00000387393.3 Q7Z3B3-1

Frequencies

GnomAD3 genomes
AF:
0.00
AC:
0
AN:
152072
Hom.:
0
Cov.:
35
FAILED QC
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:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000517
AC:
13
AN:
251432
Hom.:
0
AF XY:
0.0000515
AC XY:
7
AN XY:
135890
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000318
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000544
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000879
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000164
AC:
24
AN:
1461894
Hom.:
0
Cov.:
33
AF XY:
0.0000138
AC XY:
10
AN XY:
727248
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.000313
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000809
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Data not reliable, filtered out with message: AC0
AF:
0.00
AC:
0
AN:
152072
Hom.:
0
Cov.:
35
AF XY:
0.00
AC XY:
0
AN XY:
74274
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000108
Hom.:
0
Bravo
AF:
0.0000378
ExAC
AF:
0.0000330
AC:
4

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:2
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Koolen-de Vries syndrome Uncertain:2
Sep 18, 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 arginine with cysteine at codon 297 of the KANSL1 protein (p.Arg297Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. 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: 517800). 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 disruptive. 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. -

Aug 07, 2018
Genomic Research Center, Shahid Beheshti University of Medical Sciences
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Inborn genetic diseases Benign:1
Jan 19, 2024
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
Sep 18, 2018
GeneDx
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.96
BayesDel_addAF
Benign
-0.031
T
BayesDel_noAF
Uncertain
0.020
CADD
Pathogenic
32
DANN
Pathogenic
1.0
Eigen
Uncertain
0.49
Eigen_PC
Uncertain
0.50
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Pathogenic
0.98
.;.;.;.;D;D;D;D;D
M_CAP
Benign
0.074
D
MetaRNN
Uncertain
0.57
D;D;D;D;D;D;D;D;D
MetaSVM
Benign
-1.2
T
PrimateAI
Pathogenic
0.83
D
PROVEAN
Pathogenic
-6.1
D;.;.;.;.;D;.;.;.
REVEL
Uncertain
0.37
Sift
Pathogenic
0.0
D;.;.;.;.;D;.;.;.
Sift4G
Pathogenic
0.0010
D;D;D;.;D;D;.;.;.
Vest4
0.94
MutPred
0.48
Loss of disorder (P = 0.0114);Loss of disorder (P = 0.0114);Loss of disorder (P = 0.0114);Loss of disorder (P = 0.0114);Loss of disorder (P = 0.0114);Loss of disorder (P = 0.0114);Loss of disorder (P = 0.0114);Loss of disorder (P = 0.0114);Loss of disorder (P = 0.0114);
MVP
0.41
MPC
0.15
ClinPred
0.45
T
GERP RS
4.0
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
gMVP
0.50

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: rs772236084; hg19: chr17-44248621; API