17-46033175-G-A

Variant names:

• chr17-46033175-G-A
• rs35833914
• NM_015443.4:c.2742C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_015443.4(KANSL1):​c.2742C>T​(p.Asp914Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.188 in 1,596,188 control chromosomes in the GnomAD database, including 32,354 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (2101 hom., cov: 32)
  • Exomes 𝑓: 0.19 (30253 hom.)
• Consequence: KANSL1 NM_015443.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.334
• Publications: 30 publications found

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]

KANSL1 Gene-Disease associations (from GenCC):

• Koolen-de Vries syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), ClinGen
• Koolen-de Vries syndrome due to a point mutation

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BP6: Variant 17-46033175-G-A is Benign according to our data. Variant chr17-46033175-G-A is described in ClinVar as Benign. ClinVar VariationId is 323766.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.334 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.214 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015443.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KANSL1	NM_015443.4	MANE Select	c.2742C>T	p.Asp914Asp	synonymous	Exon 13 of 15	NP_056258.1
	KANSL1	NM_001193466.2		c.2742C>T	p.Asp914Asp	synonymous	Exon 13 of 15	NP_001180395.1
	KANSL1	NM_001379198.1		c.2742C>T	p.Asp914Asp	synonymous	Exon 14 of 16	NP_001366127.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KANSL1	ENST00000432791.7	TSL:1 MANE Select	c.2742C>T	p.Asp914Asp	synonymous	Exon 13 of 15	ENSP00000387393.3
	KANSL1	ENST00000262419.10	TSL:1	c.2742C>T	p.Asp914Asp	synonymous	Exon 13 of 15	ENSP00000262419.6
	KANSL1	ENST00000572218.5	TSL:1	n.6959C>T		non_coding_transcript_exon	Exon 6 of 8

Frequencies

GnomAD3 genomes AF: 0.143 AC: 21754 AN: 152000 Hom.: 2102 Cov.: 32

Gnomad AFR AF: 0.0429

Gnomad AMI AF: 0.276

Gnomad AMR AF: 0.176

Gnomad ASJ AF: 0.240

Gnomad EAS AF: 0.00154

Gnomad SAS AF: 0.0740

Gnomad FIN AF: 0.0650

Gnomad MID AF: 0.218

Gnomad NFE AF: 0.217

Gnomad OTH AF: 0.182

GnomAD2 exomes AF: 0.143 AC: 32274 AN: 226406 AF XY: 0.146

Gnomad AFR exome AF: 0.0387

Gnomad AMR exome AF: 0.117

Gnomad ASJ exome AF: 0.253

Gnomad EAS exome AF: 0.000634

Gnomad FIN exome AF: 0.0669

Gnomad NFE exome AF: 0.211

Gnomad OTH exome AF: 0.177

GnomAD4 exome AF: 0.193 AC: 278001 AN: 1444068 Hom.: 30253 Cov.: 32 AF XY: 0.190 AC XY: 136253 AN XY: 717028

African (AFR) AF: 0.0361 AC: 1199 AN: 33228

American (AMR) AF: 0.124 AC: 5363 AN: 43252

Ashkenazi Jewish (ASJ) AF: 0.255 AC: 6566 AN: 25732

East Asian (EAS) AF: 0.000866 AC: 34 AN: 39282

South Asian (SAS) AF: 0.0788 AC: 6617 AN: 83934

European-Finnish (FIN) AF: 0.0719 AC: 3775 AN: 52492

Middle Eastern (MID) AF: 0.201 AC: 1157 AN: 5744

European-Non Finnish (NFE) AF: 0.221 AC: 242731 AN: 1100626

Other (OTH) AF: 0.177 AC: 10559 AN: 59778

GnomAD4 genome AF: 0.143 AC: 21745 AN: 152120 Hom.: 2101 Cov.: 32 AF XY: 0.134 AC XY: 9950 AN XY: 74370

African (AFR) AF: 0.0428 AC: 1776 AN: 41522

American (AMR) AF: 0.175 AC: 2679 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.240 AC: 834 AN: 3472

East Asian (EAS) AF: 0.00154 AC: 8 AN: 5180

South Asian (SAS) AF: 0.0741 AC: 357 AN: 4818

European-Finnish (FIN) AF: 0.0650 AC: 689 AN: 10594

Middle Eastern (MID) AF: 0.214 AC: 63 AN: 294

European-Non Finnish (NFE) AF: 0.217 AC: 14710 AN: 67940

Other (OTH) AF: 0.180 AC: 378 AN: 2104

Alfa AF: 0.188 Hom.: 2338

Bravo AF: 0.148

Asia WGS AF: 0.0310 AC: 109 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Apr 20, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Syndromic intellectual disability Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

MAPT-Related Spectrum Disorders Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Koolen-de Vries syndrome Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	2.2
DANN	Benign	0.82
PhyloP100		-0.33
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs35833914; hg19: chr17-44110541;