rs17574604

Variant names:

• chr17-46034247-A-G
• rs17574604
• NM_015443.4:c.2580T>C

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.2580T>C​(p.Phe860Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.189 in 1,613,590 control chromosomes in the GnomAD database, including 32,776 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (2136 hom., cov: 32)
  • Exomes 𝑓: 0.19 (30640 hom.)
• Consequence: KANSL1 NM_015443.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.635
• Publications: 47 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=-0.82).
• BP6: Variant 17-46034247-A-G is Benign according to our data. Variant chr17-46034247-A-G is described in ClinVar as Benign. ClinVar VariationId is 323767.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.635 with no splicing effect.
• 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 rank	MANE	Protein	UniProt
KANSL1	NM_015443.4	c.2580T>C	p.Phe860Phe	synonymous_variant	Exon 11 of 15	ENST00000432791.7	NP_056258.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KANSL1	ENST00000432791.7	c.2580T>C	p.Phe860Phe	synonymous_variant	Exon 11 of 15	1	NM_015443.4	ENSP00000387393.3

Frequencies

GnomAD3 genomes AF: 0.143 AC: 21812 AN: 152136 Hom.: 2138 Cov.: 32

Gnomad AFR AF: 0.0429

Gnomad AMI AF: 0.278

Gnomad AMR AF: 0.176

Gnomad ASJ AF: 0.240

Gnomad EAS AF: 0.00154

Gnomad SAS AF: 0.0736

Gnomad FIN AF: 0.0649

Gnomad MID AF: 0.218

Gnomad NFE AF: 0.217

Gnomad OTH AF: 0.184

GnomAD2 exomes AF: 0.145 AC: 36448 AN: 251234 AF XY: 0.149

Gnomad AFR exome AF: 0.0398

Gnomad AMR exome AF: 0.119

Gnomad ASJ exome AF: 0.254

Gnomad EAS exome AF: 0.000652

Gnomad FIN exome AF: 0.0681

Gnomad NFE exome AF: 0.213

Gnomad OTH exome AF: 0.175

GnomAD4 exome AF: 0.193 AC: 282555 AN: 1461336 Hom.: 30640 Cov.: 32 AF XY: 0.191 AC XY: 138803 AN XY: 726990

African (AFR) AF: 0.0365 AC: 1221 AN: 33474

American (AMR) AF: 0.125 AC: 5597 AN: 44686

Ashkenazi Jewish (ASJ) AF: 0.256 AC: 6694 AN: 26124

East Asian (EAS) AF: 0.000882 AC: 35 AN: 39688

South Asian (SAS) AF: 0.0795 AC: 6854 AN: 86224

European-Finnish (FIN) AF: 0.0724 AC: 3867 AN: 53416

Middle Eastern (MID) AF: 0.202 AC: 1163 AN: 5768

European-Non Finnish (NFE) AF: 0.222 AC: 246452 AN: 1111584

Other (OTH) AF: 0.177 AC: 10672 AN: 60372

GnomAD4 genome AF: 0.143 AC: 21801 AN: 152254 Hom.: 2136 Cov.: 32 AF XY: 0.134 AC XY: 9973 AN XY: 74430

African (AFR) AF: 0.0428 AC: 1780 AN: 41550

American (AMR) AF: 0.175 AC: 2682 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.240 AC: 834 AN: 3470

East Asian (EAS) AF: 0.00154 AC: 8 AN: 5188

South Asian (SAS) AF: 0.0736 AC: 355 AN: 4822

European-Finnish (FIN) AF: 0.0649 AC: 689 AN: 10616

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

European-Non Finnish (NFE) AF: 0.217 AC: 14754 AN: 68000

Other (OTH) AF: 0.181 AC: 383 AN: 2112

Alfa AF: 0.198 Hom.: 4833

Bravo AF: 0.148

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: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

- -

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 v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	1.6
DANN	Benign	0.54
PhyloP100		-0.64
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)		0.080		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: rs17574604; hg19: chr17-44111613; COSMIC: COSV52274749; COSMIC: COSV52274749;