rs281865473

Variant names:

• chr17-46171157-CAA-C
• rs281865473
• NM_015443.4:c.985_986delTT

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PVS1

The NM_015443.4(KANSL1):​c.985_986delTT​(p.Leu329GlufsTer22) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000958 in 1,461,874 control chromosomes in the GnomAD database, with no homozygous occurrence. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 35)
  • Exomes 𝑓: 0.0000096 (0 hom.)
• Consequence: KANSL1 NM_015443.4 frameshift
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:2 B:1 O:1
• Conservation: PhyloP100: 6.89
• Publications: 4 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: Likely_pathogenic. The variant received 8 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KANSL1	NM_015443.4	c.985_986delTT	p.Leu329GlufsTer22	frameshift_variant	Exon 2 of 15	ENST00000432791.7	NP_056258.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KANSL1	ENST00000432791.7	c.985_986delTT	p.Leu329GlufsTer22	frameshift_variant	Exon 2 of 15	1	NM_015443.4	ENSP00000387393.3

Frequencies

GnomAD3 genomes Cov.: 35

GnomAD2 exomes AF: 0.0000278 AC: 7 AN: 251476 AF XY: 0.0000368

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000397

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000958 AC: 14 AN: 1461874 Hom.: 0 AF XY: 0.0000138 AC XY: 10 AN XY: 727238

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000306 AC: 8 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53404

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000540 AC: 6 AN: 1112010

Other (OTH) AF: 0.00 AC: 0 AN: 60396

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 35

Alfa AF: 0.000102 Hom.: 0

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:2 Benign:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Koolen-de Vries syndrome Pathogenic:2 Uncertain:1 Benign:1 Other:1

May 04, 2022

Mendelics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 02, 2024

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Sep 01, 2017

Baylor Genetics

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: clinical testing

Likely pathogenicity based on finding it twice in our laboratory: in a 7-year-old male with intellectual disability, dysmorphisms, short stature, strabismus, asymmetric prominent ventricles, possible undermylination, amygdala/hippocampal dysgenesis; in a 3-year-old feale with global delays, hypotonia, dysmorphisms, short stature, microcephaly, congenital heart disease, brain & eye anomalies. However, inheritance was not determined, and of note, the promoter and 5' exons of KANSL1 can be partially duplicated in some individuals. Exome and Sanger data could not distinguish if this change is located in the real KANSL1 gene or the duplicated copy of the gene -

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Jun 25, 2024

Genomic Medicine, Universita Cattolica del Sacro Cuore

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing;in vitro

Inherited from healthy father. Patient lacking Koolen-de Vries syndrome (KdVS) phenotype. By cDNA analysis, it has been demonstrated that the variant involves a non-functional KANSL1 pseudogene that can be found in some structural haplotypes (PMID: 22751100, PMID: 22751096, PMID: 33050294). IMPORTANT: this variant has been classified as benign in this case because it affects neither functional allele of the KANSL1 gene. it, instead, involves a duplicated genomic region that includes the first two (or three) exons of the KANSL1 transcript NM_015443.4. On the contrary, it should have been considered pathogenic if it was mapped within either functional copy of the KANSL1 gene (PMID: 26306646). It is not possible to define if the variant affects the duplicated region or the functional KANSL1 gene sequence solely on the basis of genomic DNA sequencing results. This variant is reported in the gnomAD database v4.1.0 with a frequency of 0.000005085 in non-Finnish European population (6 out of 1180044 alleles) and of 0.0002702 (8 out of 29606 alleles) in Ashkenazi Jewish population. We expect it is mismapped in those subjects (who are supposed not to be affected by KdVS) and involves the polymorphic duplication of KANSL1 exon 2. -

not provided Uncertain:1

Jun 21, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 22751096, 34356170, 20301783, 25326635, 33004838, 26306646) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		6.9
Mutation Taster		=0/200	disease causing (fs/PTC)

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: rs281865473; hg19: chr17-44248523; COSMIC: COSV52275908; COSMIC: COSV52275908;