17-46050759-A-C

Variant names:

• chr17-46050759-A-C
• rs12150447
• NM_015443.4:c.1849-55T>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_015443.4(KANSL1):​c.1849-55T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.189 in 1,529,638 control chromosomes in the GnomAD database, including 31,077 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (2131 hom., cov: 32)
  • Exomes 𝑓: 0.19 (28946 hom.)
• Consequence: KANSL1 NM_015443.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.568
• Publications: 23 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BP6: Variant 17-46050759-A-C is Benign according to our data. Variant chr17-46050759-A-C is described in ClinVar as Benign. ClinVar VariationId is 670660.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.1849-55T>G		intron	N/A	NP_056258.1
	KANSL1	NM_001193466.2		c.1849-55T>G		intron	N/A	NP_001180395.1
	KANSL1	NM_001379198.1		c.1849-55T>G		intron	N/A	NP_001366127.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KANSL1	ENST00000432791.7	TSL:1 MANE Select	c.1849-55T>G		intron	N/A	ENSP00000387393.3
	KANSL1	ENST00000262419.10	TSL:1	c.1849-55T>G		intron	N/A	ENSP00000262419.6
	KANSL1	ENST00000572904.6	TSL:5	c.1849-55T>G		intron	N/A	ENSP00000461484.1

Frequencies

GnomAD3 genomes AF: 0.143 AC: 21810 AN: 152082 Hom.: 2133 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: 0.00154

Gnomad SAS AF: 0.0741

Gnomad FIN AF: 0.0650

Gnomad MID AF: 0.218

Gnomad NFE AF: 0.217

Gnomad OTH AF: 0.184

GnomAD4 exome AF: 0.194 AC: 266729 AN: 1377438 Hom.: 28946 AF XY: 0.191 AC XY: 130194 AN XY: 681254

African (AFR) AF: 0.0367 AC: 1163 AN: 31680

American (AMR) AF: 0.127 AC: 5022 AN: 39432

Ashkenazi Jewish (ASJ) AF: 0.256 AC: 6323 AN: 24732

East Asian (EAS) AF: 0.000848 AC: 32 AN: 37726

South Asian (SAS) AF: 0.0798 AC: 6405 AN: 80280

European-Finnish (FIN) AF: 0.0724 AC: 3679 AN: 50830

Middle Eastern (MID) AF: 0.202 AC: 914 AN: 4514

European-Non Finnish (NFE) AF: 0.222 AC: 233049 AN: 1051162

Other (OTH) AF: 0.178 AC: 10142 AN: 57082

GnomAD4 genome AF: 0.143 AC: 21799 AN: 152200 Hom.: 2131 Cov.: 32 AF XY: 0.134 AC XY: 9978 AN XY: 74428

African (AFR) AF: 0.0429 AC: 1782 AN: 41546

American (AMR) AF: 0.176 AC: 2687 AN: 15294

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

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

South Asian (SAS) AF: 0.0742 AC: 358 AN: 4828

European-Finnish (FIN) AF: 0.0650 AC: 688 AN: 10592

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

European-Non Finnish (NFE) AF: 0.217 AC: 14744 AN: 67968

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

Alfa AF: 0.104 Hom.: 547

Bravo AF: 0.148

Asia WGS AF: 0.0310 AC: 109 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 14, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	2.4
DANN	Benign	0.35
PhyloP100		-0.57
PromoterAI		-0.0054	Neutral
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: rs12150447; hg19: chr17-44128125;