chr17-46171573-C-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_015443.4(KANSL1):​c.571G>T​(p.Gly191Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000666 in 1,604,922 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00039 ( 0 hom., cov: 35)
Exomes 𝑓: 0.00070 ( 0 hom. )

Consequence

KANSL1
NM_015443.4 missense

Scores

2
15

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 1.61
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 -20 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.040864676).
BP6
Variant 17-46171573-C-A is Benign according to our data. Variant chr17-46171573-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 205770.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000388 (59/152242) while in subpopulation NFE AF= 0.000647 (44/68028). AF 95% confidence interval is 0.000495. There are 0 homozygotes in gnomad4. There are 25 alleles in male gnomad4 subpopulation. Median coverage is 35. This position pass quality control queck.
BS2
High AC in GnomAd4 at 59 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
KANSL1NM_015443.4 linkc.571G>T p.Gly191Cys missense_variant 2/15 ENST00000432791.7 NP_056258.1 Q7Z3B3-1A0A024R9Y2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
KANSL1ENST00000432791.7 linkc.571G>T p.Gly191Cys missense_variant 2/151 NM_015443.4 ENSP00000387393.3 Q7Z3B3-1

Frequencies

GnomAD3 genomes
AF:
0.000388
AC:
59
AN:
152124
Hom.:
0
Cov.:
35
show subpopulations
Gnomad AFR
AF:
0.000290
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000196
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:
0.000647
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000265
AC:
64
AN:
241888
Hom.:
0
AF XY:
0.000252
AC XY:
33
AN XY:
130920
show subpopulations
Gnomad AFR exome
AF:
0.000187
Gnomad AMR exome
AF:
0.0000306
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000545
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000695
AC:
1010
AN:
1452680
Hom.:
0
Cov.:
35
AF XY:
0.000653
AC XY:
472
AN XY:
722500
show subpopulations
Gnomad4 AFR exome
AF:
0.000121
Gnomad4 AMR exome
AF:
0.0000234
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.0000189
Gnomad4 NFE exome
AF:
0.000886
Gnomad4 OTH exome
AF:
0.000367
GnomAD4 genome
AF:
0.000388
AC:
59
AN:
152242
Hom.:
0
Cov.:
35
AF XY:
0.000336
AC XY:
25
AN XY:
74418
show subpopulations
Gnomad4 AFR
AF:
0.000289
Gnomad4 AMR
AF:
0.000196
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000647
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000715
Hom.:
0
Bravo
AF:
0.000389
ESP6500AA
AF:
0.000227
AC:
1
ESP6500EA
AF:
0.000349
AC:
3
ExAC
AF:
0.000165
AC:
20

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Koolen-de Vries syndrome Benign:3
Likely benign, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesFeb 12, 2024- -
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJun 03, 2024- -
Likely benign, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsJul 19, 2021- -
not provided Benign:2
Benign, criteria provided, single submitterclinical testingGeneDxJan 21, 2021- -
Likely benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenJun 01, 2023KANSL1: BP4 -
not specified Benign:1
Likely benign, criteria provided, single submitterclinical testingAthena DiagnosticsJun 22, 2017- -
Inborn genetic diseases Benign:1
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsJan 04, 2022This 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.094
BayesDel_addAF
Benign
-0.46
T
BayesDel_noAF
Benign
-0.51
CADD
Benign
14
DANN
Uncertain
0.98
Eigen
Benign
-0.28
Eigen_PC
Benign
-0.21
FATHMM_MKL
Uncertain
0.81
D
LIST_S2
Benign
0.70
.;.;.;.;T;T;T;T;T
M_CAP
Benign
0.016
T
MetaRNN
Benign
0.041
T;T;T;T;T;T;T;T;T
MetaSVM
Benign
-1.0
T
PrimateAI
Benign
0.34
T
PROVEAN
Benign
-0.79
N;.;.;.;.;N;.;.;.
REVEL
Benign
0.086
Sift
Benign
0.096
T;.;.;.;.;T;.;.;.
Sift4G
Benign
0.078
T;T;T;.;D;T;.;.;.
Vest4
0.32
MVP
0.20
MPC
0.073
ClinPred
0.027
T
GERP RS
3.0
gMVP
0.19

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: rs149566146; hg19: chr17-44248939; API