rs35643216

chr17-46171471-T-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.673A>G(p.Asn225Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.148 in 1,568,724 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N225S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.11 (0 hom., cov: 35)
  • Exomes 𝑓: 0.15 (0 hom.)
• Consequence: KANSL1 NM_015443.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.62

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=0.001316905).
• BP6: Variant 17-46171471-T-C is Benign according to our data. Variant chr17-46171471-T-C is described in ClinVar as [Benign]. Clinvar id is 323790.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-46171471-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.171 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KANSL1	NM_015443.4	c.673A>G	p.Asn225Asp	missense_variant	2/15	ENST00000432791.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KANSL1	ENST00000432791.7	c.673A>G	p.Asn225Asp	missense_variant	2/15	1	NM_015443.4	P4

Frequencies

GnomAD3 genomes AF: 0.115 AC: 17185 AN: 149994 Hom.: 0 Cov.: 35

Gnomad AFR AF: 0.0345

Gnomad AMI AF: 0.248

Gnomad AMR AF: 0.143

Gnomad ASJ AF: 0.181

Gnomad EAS AF: 0.00116

Gnomad SAS AF: 0.0529

Gnomad FIN AF: 0.0564

Gnomad MID AF: 0.171

Gnomad NFE AF: 0.174

Gnomad OTH AF: 0.149

GnomAD3 exomes AF: 0.113 AC: 27969 AN: 246450 Hom.: 0 AF XY: 0.115 AC XY: 15271 AN XY: 133046

Gnomad AFR exome AF: 0.0318

Gnomad AMR exome AF: 0.0983

Gnomad ASJ exome AF: 0.177

Gnomad EAS exome AF: 0.000598

Gnomad SAS exome AF: 0.0506

Gnomad FIN exome AF: 0.0583

Gnomad NFE exome AF: 0.170

Gnomad OTH exome AF: 0.139

GnomAD4 exome AF: 0.152 AC: 215603 AN: 1418612 Hom.: 0 Cov.: 49 AF XY: 0.150 AC XY: 105724 AN XY: 706244

Gnomad4 AFR exome AF: 0.0296

Gnomad4 AMR exome AF: 0.104

Gnomad4 ASJ exome AF: 0.188

Gnomad4 EAS exome AF: 0.000831

Gnomad4 SAS exome AF: 0.0550

Gnomad4 FIN exome AF: 0.0650

Gnomad4 NFE exome AF: 0.175

Gnomad4 OTH exome AF: 0.141

GnomAD4 genome AF: 0.114 AC: 17172 AN: 150112 Hom.: 0 Cov.: 35 AF XY: 0.107 AC XY: 7852 AN XY: 73394

Gnomad4 AFR AF: 0.0344

Gnomad4 AMR AF: 0.143

Gnomad4 ASJ AF: 0.181

Gnomad4 EAS AF: 0.00116

Gnomad4 SAS AF: 0.0527

Gnomad4 FIN AF: 0.0564

Gnomad4 NFE AF: 0.174

Gnomad4 OTH AF: 0.147

Alfa AF: 0.161 Hom.: 3

ESP6500AA AF: 0.0379 AC: 167

ESP6500EA AF: 0.182 AC: 1565

ExAC AF: 0.120 AC: 14625

Asia WGS AF: 0.0250 AC: 87 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	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 20, 2017	- -

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	21
Dann	Uncertain	0.99
Eigen	Benign	-0.071
Eigen_PC	Benign	0.14
FATHMM_MKL	Uncertain	0.90	D
MetaRNN	Benign	0.0013	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.71	T
MutationTaster	Benign	1.0	D;N;N;N;N;N
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-0.33	N;.;.;.;.;N;.;.;.
REVEL	Benign	0.058
Sift	Benign	0.14	T;.;.;.;.;T;.;.;.
Sift4G	Benign	0.64	T;T;T;.;T;T;.;.;.
Vest4		0.20
MPC		0.020
ClinPred		0.0047	T
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.13

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: rs35643216; hg19: chr17-44248837; COSMIC: COSV52264978; COSMIC: COSV52264978;