rs7220988

Positions:

• chr17-46032108-G-A

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.3029C>T​(p.Pro1010Leu) variant causes a missense change. The variant allele was found at a frequency of 0.388 in 1,613,746 control chromosomes in the GnomAD database, including 126,362 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P1010A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.35 (9606 hom., cov: 31)
  • Exomes 𝑓: 0.39 (116756 hom.)
• Consequence: KANSL1 NM_015443.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 4.16

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=5.3045103E-5).
• BP6: Variant 17-46032108-G-A is Benign according to our data. Variant chr17-46032108-G-A is described in ClinVar as [Benign]. Clinvar id is 323764.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-46032108-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.558 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KANSL1	NM_015443.4	c.3029C>T	p.Pro1010Leu	missense_variant	14/15	ENST00000432791.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KANSL1	ENST00000432791.7	c.3029C>T	p.Pro1010Leu	missense_variant	14/15	1	NM_015443.4	P4

Frequencies

GnomAD3 genomes AF: 0.346 AC: 52500 AN: 151788 Hom.: 9611 Cov.: 31

Gnomad AFR AF: 0.257

Gnomad AMI AF: 0.200

Gnomad AMR AF: 0.273

Gnomad ASJ AF: 0.433

Gnomad EAS AF: 0.113

Gnomad SAS AF: 0.576

Gnomad FIN AF: 0.432

Gnomad MID AF: 0.277

Gnomad NFE AF: 0.403

Gnomad OTH AF: 0.327

GnomAD3 exomes AF: 0.375 AC: 94222 AN: 251322 Hom.: 19499 AF XY: 0.390 AC XY: 53007 AN XY: 135820

Gnomad AFR exome AF: 0.252

Gnomad AMR exome AF: 0.275

Gnomad ASJ exome AF: 0.415

Gnomad EAS exome AF: 0.114

Gnomad SAS exome AF: 0.577

Gnomad FIN exome AF: 0.437

Gnomad NFE exome AF: 0.396

Gnomad OTH exome AF: 0.367

GnomAD4 exome AF: 0.392 AC: 573248 AN: 1461838 Hom.: 116756 Cov.: 56 AF XY: 0.399 AC XY: 289904 AN XY: 727222

Gnomad4 AFR exome AF: 0.253

Gnomad4 AMR exome AF: 0.280

Gnomad4 ASJ exome AF: 0.414

Gnomad4 EAS exome AF: 0.106

Gnomad4 SAS exome AF: 0.567

Gnomad4 FIN exome AF: 0.436

Gnomad4 NFE exome AF: 0.396

Gnomad4 OTH exome AF: 0.387

GnomAD4 genome AF: 0.346 AC: 52510 AN: 151908 Hom.: 9606 Cov.: 31 AF XY: 0.347 AC XY: 25770 AN XY: 74220

Gnomad4 AFR AF: 0.257

Gnomad4 AMR AF: 0.273

Gnomad4 ASJ AF: 0.433

Gnomad4 EAS AF: 0.113

Gnomad4 SAS AF: 0.576

Gnomad4 FIN AF: 0.432

Gnomad4 NFE AF: 0.403

Gnomad4 OTH AF: 0.323

Alfa AF: 0.386 Hom.: 25240

Bravo AF: 0.321

TwinsUK AF: 0.389 AC: 1442

ALSPAC AF: 0.392 AC: 1510

ESP6500AA AF: 0.248 AC: 1093

ESP6500EA AF: 0.397 AC: 3412

ExAC AF: 0.377 AC: 45777

Asia WGS AF: 0.354 AC: 1231 AN: 3478

EpiCase AF: 0.391

EpiControl AF: 0.386

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Koolen-de Vries syndrome Benign:3

Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Sep 20, 2021	- -

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: 23909765) -

Syndromic intellectual disability Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

MAPT-Related Spectrum Disorders Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.051
BayesDel_addAF	Benign	-0.73	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	18
DANN	Benign	0.94
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.21
FATHMM_MKL	Benign	0.35	N
LIST_S2	Benign	0.57	.;.;.;.;T;T;T
MetaRNN	Benign	0.000053	T;T;T;T;T;T;T
MetaSVM	Benign	-0.94	T
MutationTaster	Benign	0.24	P;P;P;P;P;P
PrimateAI	Benign	0.35	T
PROVEAN	Benign	0.65	N;.;.;.;.;N;.
REVEL	Benign	0.058
Sift	Benign	0.74	T;.;.;.;.;T;.
Sift4G	Benign	0.56	.;T;.;.;T;T;.
Vest4		0.028, 0.041, 0.027
MPC		0.47
ClinPred		0.0099	T
GERP RS		4.6
gMVP		0.054

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: rs7220988; hg19: chr17-44109474; COSMIC: COSV52236722; COSMIC: COSV52236722;