rs281865473
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 8P and 4B. PVS1BS2
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. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_015443.4 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
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
Frequencies
GnomAD3 genomes Cov.: 35
GnomAD3 exomes AF: 0.0000278 AC: 7AN: 251476Hom.: 0 AF XY: 0.0000368 AC XY: 5AN XY: 135918
GnomAD4 exome AF: 0.00000958 AC: 14AN: 1461874Hom.: 0 AF XY: 0.0000138 AC XY: 10AN XY: 727238
GnomAD4 genome Cov.: 35
ClinVar
Submissions by phenotype
Koolen-de Vries syndrome Pathogenic:2Uncertain:1Benign:1Other:1
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. -
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 -
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not provided Uncertain:1
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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at