rs34579536

Positions:

• chr17-46031540-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.3254T>C​(p.Ile1085Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.189 in 1,613,758 control chromosomes in the GnomAD database, including 32,754 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (2129 hom., cov: 32)
  • Exomes 𝑓: 0.19 (30625 hom.)
• Consequence: KANSL1 NM_015443.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.905

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=0.0036968887).
• BP6: Variant 17-46031540-A-G is Benign according to our data. Variant chr17-46031540-A-G is described in ClinVar as [Benign]. Clinvar id is 323762.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-46031540-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.3254T>C	p.Ile1085Thr	missense_variant	15/15	ENST00000432791.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KANSL1	ENST00000432791.7	c.3254T>C	p.Ile1085Thr	missense_variant	15/15	1	NM_015443.4	P4

Frequencies

GnomAD3 genomes AF: 0.143 AC: 21803 AN: 152076 Hom.: 2131 Cov.: 32

Gnomad AFR AF: 0.0430

Gnomad AMI AF: 0.277

Gnomad AMR AF: 0.176

Gnomad ASJ AF: 0.240

Gnomad EAS AF: 0.00155

Gnomad SAS AF: 0.0733

Gnomad FIN AF: 0.0651

Gnomad MID AF: 0.218

Gnomad NFE AF: 0.217

Gnomad OTH AF: 0.184

GnomAD3 exomes AF: 0.144 AC: 36044 AN: 249624 Hom.: 3451 AF XY: 0.148 AC XY: 20013 AN XY: 135216

Gnomad AFR exome AF: 0.0397

Gnomad AMR exome AF: 0.118

Gnomad ASJ exome AF: 0.254

Gnomad EAS exome AF: 0.000654

Gnomad SAS exome AF: 0.0759

Gnomad FIN exome AF: 0.0674

Gnomad NFE exome AF: 0.212

Gnomad OTH exome AF: 0.175

GnomAD4 exome AF: 0.193 AC: 282680 AN: 1461564 Hom.: 30625 Cov.: 33 AF XY: 0.191 AC XY: 138830 AN XY: 727042

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: 0.0723

Gnomad4 NFE exome AF: 0.222

Gnomad4 OTH exome AF: 0.177

GnomAD4 genome AF: 0.143 AC: 21792 AN: 152194 Hom.: 2129 Cov.: 32 AF XY: 0.134 AC XY: 9972 AN XY: 74408

Gnomad4 AFR AF: 0.0429

Gnomad4 AMR AF: 0.176

Gnomad4 ASJ AF: 0.240

Gnomad4 EAS AF: 0.00155

Gnomad4 SAS AF: 0.0734

Gnomad4 FIN AF: 0.0651

Gnomad4 NFE AF: 0.217

Gnomad4 OTH AF: 0.181

Alfa AF: 0.203 Hom.: 5446

Bravo AF: 0.148

TwinsUK AF: 0.233 AC: 865

ALSPAC AF: 0.242 AC: 931

ESP6500AA AF: 0.0461 AC: 203

ESP6500EA AF: 0.223 AC: 1914

ExAC AF: 0.143 AC: 17393

Asia WGS AF: 0.0310 AC: 109 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

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) -

MAPT-Related Spectrum Disorders Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

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	0.064
BayesDel_addAF	Benign	-0.82	T
BayesDel_noAF	Benign	-0.81
CADD	Benign	3.2
DANN	Benign	0.64
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.33	N
LIST_S2	Benign	0.045	.;.;.;.;T;T;T
MetaRNN	Benign	0.0037	T;T;T;T;T;T;T
MetaSVM	Benign	-0.97	T
MutationTaster	Benign	1.0	P;P;P;P;P;P
PrimateAI	Benign	0.32	T
PROVEAN	Benign	0.25	N;.;.;.;.;N;.
REVEL	Benign	0.032
Sift	Benign	0.40	T;.;.;.;.;T;.
Sift4G	Uncertain	0.020	.;D;.;.;T;D;.
Vest4		0.0060, 0.022, 0.0050
MPC		0.58
ClinPred		0.00062	T
GERP RS		2.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
gMVP		0.043

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: rs34579536; hg19: chr17-44108906;