rs587783916
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PP2PP3BS1_SupportingBS2
The NM_133433.4(NIPBL):āc.3109A>Gā(p.Lys1037Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000442 in 1,356,362 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 Uncertain significance (ā ā ).
Frequency
Consequence
NM_133433.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -3 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
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NIPBL | ENST00000282516.13 | c.3109A>G | p.Lys1037Glu | missense_variant | Exon 10 of 47 | 1 | NM_133433.4 | ENSP00000282516.8 | ||
NIPBL | ENST00000448238.2 | c.3109A>G | p.Lys1037Glu | missense_variant | Exon 10 of 46 | 1 | ENSP00000406266.2 | |||
NIPBL | ENST00000652901.1 | c.3109A>G | p.Lys1037Glu | missense_variant | Exon 10 of 46 | ENSP00000499536.1 | ||||
NIPBL | ENST00000504430.5 | n.2729A>G | non_coding_transcript_exon_variant | Exon 6 of 8 | 2 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.00000590 AC: 1AN: 169396Hom.: 0 AF XY: 0.0000110 AC XY: 1AN XY: 90646
GnomAD4 exome AF: 0.00000442 AC: 6AN: 1356362Hom.: 0 Cov.: 28 AF XY: 0.00000600 AC XY: 4AN XY: 667090
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Cornelia de Lange syndrome 1 Uncertain:4
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This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 1037 of the NIPBL protein (p.Lys1037Glu). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with NIPBL-related conditions. ClinVar contains an entry for this variant (Variation ID: 159072). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on NIPBL protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
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not provided Uncertain:1
A variant of unknown significance has been identified in the NIPBL gene. The K1037E variant has not been published as a pathogenic variant, nor has it been reported as a benign polymorphism to our knowledge. It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The K1037E variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is highly conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. However, missense mutations in nearby residues have not been reported in the Human Gene Mutation Database in association with NIPBL-related disorders (Stenson et al., 2009). Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at