NM_015443.4:c.1042C>T

Variant names:

• chr17-46171102-G-A
• rs1427624649
• NM_015443.4:c.1042C>T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_015443.4(KANSL1):​c.1042C>T​(p.Arg348*) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000205 in 1,461,852 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 35)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: KANSL1 NM_015443.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 4.54

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-46171102-G-A is Pathogenic according to our data. Variant chr17-46171102-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 521688.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KANSL1	NM_015443.4	c.1042C>T	p.Arg348*	stop_gained	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.1042C>T	p.Arg348*	stop_gained	Exon 2 of 15	1	NM_015443.4	ENSP00000387393.3

Frequencies

GnomAD3 genomes Cov.: 35

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461852 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 727236

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 35

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Koolen-de Vries syndrome Pathogenic:4

-

Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

A known stop-gain variant, c.1042C>T in exon 2 of KANSL1 was observed in heterozygous state in the Proband (Zhang et al., 2024; Zollino et al., 2015). Sanger validation and segregation analysis showed that the variant was present in heterozygous state in the proband and absent in the proband's parents. The variant is present in three individuals in heterozygous state and absent in homozygous state in gnomAD (v4.1.0). The variant is not present in homozygous and/or heterozygous state in our in-house database of 3464 exomes. This variant is likely to result in a premature truncation of the transcript that can either lead to nonsense-mediated mRNA decay or the formation of a truncated protein product. -

May 31, 2018

Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

[ACMG/AMP: PVS1, PS2, PM2, PP5] This alteration is a null variant in a gene where LOF is a known mechanism of disease [PVS1], is de novo in origin as it was not detected in the submitted parental specimens (identity confirmed) [PS2], is absent from or rarely observed in large-scale population databases [PM2], was reported as a pathogenic/likely pathogenic alteration by a reputable source (ClinVar or other correspondence from a clinical testing laboratory) [PP5]. -

Jun 05, 2019

SIB Swiss Institute of Bioinformatics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

This variant is interpreted as a Pathogenic for Koolen-De Vries syndrome, autosomal dominant. The following ACMG Tag(s) were applied: PM2: Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PM6: Assumed de novo, but without confirmation of paternity and maternity. PVS1: Predicted nullvariant in a gene where LOF is a known mechanism of disease. -

Aug 30, 2021

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases Pathogenic:1

Apr 05, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1042C>T (p.R348*) alteration, located in exon 2 (coding exon 1) of the KANSL1 gene, consists of a C to T substitution at nucleotide position 1042. This changes the amino acid from an arginine (R) to a stop codon at amino acid position 348. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been detected in multiple individuals with Koolen-de Vries syndrome, including multiple cases of reported de novo occurrence (Zollino, 2015; Miller, 2020; St John, 2022). Based on the available evidence, this alteration is classified as pathogenic. -

Intellectual disability Pathogenic:1

Apr 20, 2020

Diagnostic Laboratory, Strasbourg University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.51
CADD	Pathogenic	44
DANN	Uncertain	1.0
Eigen	Pathogenic	0.71
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Uncertain	0.90	D
Vest4		0.36
GERP RS		4.0

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

Publications

LitVar

Other links and lift over

dbSNP: rs1427624649; hg19: chr17-44248468; COSMIC: COSV52269520; COSMIC: COSV52269520;