17-46082483-T-C

Variant names:

• chr17-46082483-T-C
• rs17576165
• NM_015443.4:c.1491A>G

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.1491A>G​(p.Pro497Pro) 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 1,608,230 control chromosomes in the GnomAD database, including 32,601 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P497P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.14 (2128 hom., cov: 31)
  • Exomes 𝑓: 0.19 (30473 hom.)
• Consequence: KANSL1 NM_015443.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.0350
• Publications: 27 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=-0.54).
• BP6: Variant 17-46082483-T-C is Benign according to our data. Variant chr17-46082483-T-C is described in ClinVar as Benign. ClinVar VariationId is 323781.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.035 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.1491A>G	p.Pro497Pro	synonymous_variant	Exon 4 of 15	ENST00000432791.7	NP_056258.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KANSL1	ENST00000432791.7	c.1491A>G	p.Pro497Pro	synonymous_variant	Exon 4 of 15	1	NM_015443.4	ENSP00000387393.3

Frequencies

GnomAD3 genomes AF: 0.143 AC: 21791 AN: 151904 Hom.: 2130 Cov.: 31

Gnomad AFR AF: 0.0430

Gnomad AMI AF: 0.278

Gnomad AMR AF: 0.176

Gnomad ASJ AF: 0.240

Gnomad EAS AF: 0.00154

Gnomad SAS AF: 0.0735

Gnomad FIN AF: 0.0652

Gnomad MID AF: 0.218

Gnomad NFE AF: 0.217

Gnomad OTH AF: 0.184

GnomAD2 exomes AF: 0.144 AC: 36080 AN: 250218 AF XY: 0.148

Gnomad AFR exome AF: 0.0393

Gnomad AMR exome AF: 0.117

Gnomad ASJ exome AF: 0.253

Gnomad EAS exome AF: 0.000598

Gnomad FIN exome AF: 0.0679

Gnomad NFE exome AF: 0.213

Gnomad OTH exome AF: 0.172

GnomAD4 exome AF: 0.192 AC: 280004 AN: 1456208 Hom.: 30473 Cov.: 30 AF XY: 0.190 AC XY: 137597 AN XY: 724562

African (AFR) AF: 0.0361 AC: 1208 AN: 33420

American (AMR) AF: 0.124 AC: 5546 AN: 44582

Ashkenazi Jewish (ASJ) AF: 0.256 AC: 6660 AN: 26052

East Asian (EAS) AF: 0.000882 AC: 35 AN: 39686

South Asian (SAS) AF: 0.0787 AC: 6765 AN: 85982

European-Finnish (FIN) AF: 0.0723 AC: 3860 AN: 53394

Middle Eastern (MID) AF: 0.201 AC: 1158 AN: 5758

European-Non Finnish (NFE) AF: 0.221 AC: 244177 AN: 1107116

Other (OTH) AF: 0.176 AC: 10595 AN: 60218

GnomAD4 genome AF: 0.143 AC: 21780 AN: 152022 Hom.: 2128 Cov.: 31 AF XY: 0.134 AC XY: 9966 AN XY: 74306

African (AFR) AF: 0.0429 AC: 1778 AN: 41478

American (AMR) AF: 0.176 AC: 2685 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.240 AC: 832 AN: 3466

East Asian (EAS) AF: 0.00155 AC: 8 AN: 5170

South Asian (SAS) AF: 0.0735 AC: 354 AN: 4814

European-Finnish (FIN) AF: 0.0652 AC: 688 AN: 10550

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

European-Non Finnish (NFE) AF: 0.217 AC: 14737 AN: 67952

Other (OTH) AF: 0.181 AC: 382 AN: 2108

Alfa AF: 0.189 Hom.: 3140

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	-0.54
CADD	Benign	8.5
DANN	Benign	0.72
PhyloP100		-0.035
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs17576165; hg19: chr17-44159849;