rs17662853

Positions:

• chr17-46171482-G-A
• chr17-46171482-G-C

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.662C>T​(p.Thr221Ile) variant causes a missense change. The variant allele was found at a frequency of 0.151 in 1,608,748 control chromosomes in the GnomAD database, including 20,799 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (1230 hom., cov: 35)
  • Exomes 𝑓: 0.16 (19569 hom.)
• Consequence: KANSL1 NM_015443.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 4.54

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=9.5272064E-4).
• BP6: Variant 17-46171482-G-A is Benign according to our data. Variant chr17-46171482-G-A is described in ClinVar as [Benign]. Clinvar id is 323791.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-46171482-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.155 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KANSL1	NM_015443.4	c.662C>T	p.Thr221Ile	missense_variant	2/15	ENST00000432791.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KANSL1	ENST00000432791.7	c.662C>T	p.Thr221Ile	missense_variant	2/15	1	NM_015443.4	P4

Frequencies

GnomAD3 genomes AF: 0.107 AC: 16280 AN: 151682 Hom.: 1230 Cov.: 35

Gnomad AFR AF: 0.0259

Gnomad AMI AF: 0.311

Gnomad AMR AF: 0.0708

Gnomad ASJ AF: 0.0803

Gnomad EAS AF: 0.00193

Gnomad SAS AF: 0.0828

Gnomad FIN AF: 0.218

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.157

Gnomad OTH AF: 0.0916

GnomAD3 exomes AF: 0.117 AC: 29267 AN: 250096 Hom.: 2337 AF XY: 0.119 AC XY: 16144 AN XY: 135118

Gnomad AFR exome AF: 0.0257

Gnomad AMR exome AF: 0.0440

Gnomad ASJ exome AF: 0.0771

Gnomad EAS exome AF: 0.000652

Gnomad SAS exome AF: 0.0959

Gnomad FIN exome AF: 0.212

Gnomad NFE exome AF: 0.162

Gnomad OTH exome AF: 0.117

GnomAD4 exome AF: 0.155 AC: 226190 AN: 1456948 Hom.: 19569 Cov.: 50 AF XY: 0.153 AC XY: 110776 AN XY: 724644

Gnomad4 AFR exome AF: 0.0212

Gnomad4 AMR exome AF: 0.0471

Gnomad4 ASJ exome AF: 0.0799

Gnomad4 EAS exome AF: 0.000554

Gnomad4 SAS exome AF: 0.0991

Gnomad4 FIN exome AF: 0.215

Gnomad4 NFE exome AF: 0.174

Gnomad4 OTH exome AF: 0.132

GnomAD4 genome AF: 0.107 AC: 16277 AN: 151800 Hom.: 1230 Cov.: 35 AF XY: 0.108 AC XY: 8041 AN XY: 74194

Gnomad4 AFR AF: 0.0258

Gnomad4 AMR AF: 0.0707

Gnomad4 ASJ AF: 0.0803

Gnomad4 EAS AF: 0.00193

Gnomad4 SAS AF: 0.0829

Gnomad4 FIN AF: 0.218

Gnomad4 NFE AF: 0.157

Gnomad4 OTH AF: 0.0906

Alfa AF: 0.134 Hom.: 2008

Bravo AF: 0.0940

TwinsUK AF: 0.176 AC: 651

ALSPAC AF: 0.172 AC: 662

ESP6500AA AF: 0.0322 AC: 142

ESP6500EA AF: 0.153 AC: 1314

ExAC AF: 0.123 AC: 14919

Asia WGS AF: 0.0380 AC: 130 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Koolen-de Vries syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	22
DANN	Uncertain	0.98
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.19
FATHMM_MKL	Uncertain	0.91	D
MetaRNN	Benign	0.00095	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.95	T
MutationTaster	Benign	1.0	P;P;P;P;P;P
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-0.59	N;.;.;.;.;N;.;.;.
REVEL	Benign	0.094
Sift	Uncertain	0.0090	D;.;.;.;.;D;.;.;.
Sift4G	Benign	0.17	T;T;T;.;T;T;.;.;.
Vest4		0.53
MPC		0.099
ClinPred		0.020	T
GERP RS		3.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.26

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

Other links and lift over

dbSNP: rs17662853; hg19: chr17-44248848; COSMIC: COSV52266840; COSMIC: COSV52266840;