rs34043286

chr17-46039753-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_015443.4(KANSL1):c.2152T>C(p.Ser718Pro) variant causes a missense change. The variant allele was found at a frequency of 0.189 in 1,614,026 control chromosomes in the GnomAD database, including 32,774 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (2131 hom., cov: 33)
  • Exomes 𝑓: 0.19 (30643 hom.)
• Consequence: KANSL1 NM_015443.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 5.04

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0010493994).
• BP6: Variant 17-46039753-A-G is Benign according to our data. Variant chr17-46039753-A-G is described in ClinVar as [Benign]. Clinvar id is 323774.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-46039753-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.214 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KANSL1	NM_015443.4	c.2152T>C	p.Ser718Pro	missense_variant	8/15	ENST00000432791.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KANSL1	ENST00000432791.7	c.2152T>C	p.Ser718Pro	missense_variant	8/15	1	NM_015443.4	P4

Frequencies

GnomAD3 genomes AF: 0.143 AC: 21811 AN: 152118 Hom.: 2133 Cov.: 33

Gnomad AFR AF: 0.0429

Gnomad AMI AF: 0.277

Gnomad AMR AF: 0.176

Gnomad ASJ AF: 0.240

Gnomad EAS AF: 0.00154

Gnomad SAS AF: 0.0739

Gnomad FIN AF: 0.0649

Gnomad MID AF: 0.218

Gnomad NFE AF: 0.217

Gnomad OTH AF: 0.185

GnomAD3 exomes AF: 0.145 AC: 36480 AN: 251370 Hom.: 3543 AF XY: 0.149 AC XY: 20193 AN XY: 135858

Gnomad AFR exome AF: 0.0398

Gnomad AMR exome AF: 0.119

Gnomad ASJ exome AF: 0.254

Gnomad EAS exome AF: 0.000653

Gnomad SAS exome AF: 0.0760

Gnomad FIN exome AF: 0.0680

Gnomad NFE exome AF: 0.214

Gnomad OTH exome AF: 0.175

GnomAD4 exome AF: 0.193 AC: 282744 AN: 1461790 Hom.: 30643 Cov.: 32 AF XY: 0.191 AC XY: 138889 AN XY: 727196

Gnomad4 AFR exome AF: 0.0365

Gnomad4 AMR exome AF: 0.125

Gnomad4 ASJ exome AF: 0.256

Gnomad4 EAS exome AF: 0.000882

Gnomad4 SAS exome AF: 0.0795

Gnomad4 FIN exome AF: 0.0724

Gnomad4 NFE exome AF: 0.222

Gnomad4 OTH exome AF: 0.177

GnomAD4 genome AF: 0.143 AC: 21800 AN: 152236 Hom.: 2131 Cov.: 33 AF XY: 0.134 AC XY: 9979 AN XY: 74438

Gnomad4 AFR AF: 0.0428

Gnomad4 AMR AF: 0.176

Gnomad4 ASJ AF: 0.240

Gnomad4 EAS AF: 0.00154

Gnomad4 SAS AF: 0.0739

Gnomad4 FIN AF: 0.0649

Gnomad4 NFE AF: 0.217

Gnomad4 OTH AF: 0.182

Alfa AF: 0.201 Hom.: 4936

Bravo AF: 0.148

TwinsUK AF: 0.233 AC: 864

ALSPAC AF: 0.242 AC: 931

ESP6500AA AF: 0.0458 AC: 202

ESP6500EA AF: 0.224 AC: 1927

ExAC AF: 0.144 AC: 17507

Asia WGS AF: 0.0310 AC: 109 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 20, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 23222517) -

Koolen-de Vries syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.047
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.61
Cadd	Benign	17
Dann	Benign	0.79
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.26
FATHMM_MKL	Benign	0.092	N
MetaRNN	Benign	0.0010	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.97	T
MutationTaster	Benign	1.0	P;P;P;P;P;P
PrimateAI	Benign	0.41	T
PROVEAN	Benign	0.51	N;.;.;.;.;N;.;.;.
REVEL	Benign	0.14
Sift	Benign	1.0	T;.;.;.;.;T;.;.;.
Sift4G	Benign	0.44	T;T;T;.;T;T;.;.;.
Vest4		0.018
MPC		0.58
ClinPred		0.0059	T
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
gMVP		0.14

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

Other links and lift over

dbSNP: rs34043286; hg19: chr17-44117119; COSMIC: COSV52271806; COSMIC: COSV52271806;