17-46171537-C-G

Position:

chr17-46171537-C-G

Variant summary

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

The NM_015443.4(KANSL1):c.607G>C(p.Gly203Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000342 in 1,612,532 control chromosomes in the GnomAD database, including 2 homozygotes. 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 (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G203V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0017 ( 1 hom., cov: 35)

Exomes 𝑓: 0.00021 ( 1 hom. )

Consequence

KANSL1
NM_015443.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.310

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0055753887).

BP6

Variant 17-46171537-C-G is Benign according to our data. Variant chr17-46171537-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 323794.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00166 (252/152230) while in subpopulation AFR AF= 0.00583 (242/41502). AF 95% confidence interval is 0.00523. There are 1 homozygotes in gnomad4. There are 104 alleles in male gnomad4 subpopulation. Median coverage is 35. This position pass quality control queck.

BS2

High AC in GnomAd4 at 252 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KANSL1	NM_015443.4 linkuse as main transcript	c.607G>C	p.Gly203Arg	missense_variant	2/15	ENST00000432791.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KANSL1	ENST00000432791.7 linkuse as main transcript	c.607G>C	p.Gly203Arg	missense_variant	2/15	1	NM_015443.4	P4

Frequencies

GnomAD3 genomes

AF:

0.00166

AC:

252

AN:

152112

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00585

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000458

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000955

GnomAD3 exomes

AF:

0.000441

AC:

110

AN:

249330

Hom.:

AF XY:

0.000304

AC XY:

AN XY:

134840

show subpopulations

Gnomad AFR exome

AF:

0.00555

Gnomad AMR exome

AF:

0.000322

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000546

Gnomad SAS exome

AF:

0.0000329

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000266

Gnomad OTH exome

AF:

0.000660

GnomAD4 exome

AF:

0.000205

AC:

300

AN:

1460302

Hom.:

Cov.:

AF XY:

0.000162

AC XY:

118

AN XY:

726472

show subpopulations

Gnomad4 AFR exome

AF:

0.00655

Gnomad4 AMR exome

AF:

0.000337

Gnomad4 ASJ exome

AF:

0.0000769

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000929

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000243

Gnomad4 OTH exome

AF:

0.000398

GnomAD4 genome

AF:

0.00166

AC:

252

AN:

152230

Hom.:

Cov.:

AF XY:

0.00140

AC XY:

104

AN XY:

74420

show subpopulations

Gnomad4 AFR

AF:

0.00583

Gnomad4 AMR

AF:

0.000458

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:

0.000945

Alfa

AF:

0.000136

Hom.:

Bravo

AF:

0.00203

ESP6500AA

AF:

0.00522

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000519

AC:

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 29, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2023	KANSL1: BP4, BS1 -
Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jun 16, 2017	- -

Koolen-de Vries syndrome

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jul 26, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Aug 30, 2023	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 08, 2016

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.48

CADD

Benign

DANN

Uncertain

0.99

Eigen

Benign

-0.17

Eigen_PC

Benign

0.060

FATHMM_MKL

Uncertain

0.87

M_CAP

Benign

0.015

MetaRNN

Benign

0.0056

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

MetaSVM

Benign

-0.88

MutationTaster

Benign

1.0

D;N;N;N;N;N

PrimateAI

Benign

0.45

PROVEAN

Benign

-0.95

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

REVEL

Benign

0.12

Sift

Uncertain

0.029

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

Sift4G

Benign

0.48

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

Vest4

0.21

MutPred

0.10

Loss of relative solvent accessibility (P = 0.0676);Loss of relative solvent accessibility (P = 0.0676);Loss of relative solvent accessibility (P = 0.0676);Loss of relative solvent accessibility (P = 0.0676);Loss of relative solvent accessibility (P = 0.0676);Loss of relative solvent accessibility (P = 0.0676);Loss of relative solvent accessibility (P = 0.0676);Loss of relative solvent accessibility (P = 0.0676);Loss of relative solvent accessibility (P = 0.0676);

MVP

0.082

MPC

0.021

ClinPred

0.026

GERP RS

6.0

gMVP

0.16

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over