rs587784039
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2PM5PP2PP3_StrongPP5_Moderate
The NM_133433.4(NIPBL):c.7306G>A(p.Ala2436Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A2436V) has been classified as Pathogenic.
Frequency
Consequence
NM_133433.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 11 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
NIPBL | ENST00000282516.13 | c.7306G>A | p.Ala2436Thr | missense_variant | Exon 43 of 47 | 1 | NM_133433.4 | ENSP00000282516.8 | ||
NIPBL | ENST00000448238.2 | c.7306G>A | p.Ala2436Thr | missense_variant | Exon 43 of 46 | 1 | ENSP00000406266.2 | |||
NIPBL | ENST00000652901.1 | c.7264-1663G>A | intron_variant | Intron 42 of 45 | ENSP00000499536.1 | |||||
NIPBL | ENST00000514335.1 | n.1188G>A | non_coding_transcript_exon_variant | Exon 3 of 7 | 2 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 31
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Cornelia de Lange syndrome 1 Pathogenic:2
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The variant is not observed in the gnomAD v2.1.1 dataset. Predicted Consequence/Location: Missense variant In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.92 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.86 (>=0.6, sensitivity 0.72 and precision 0.9)]. Same nucleotide change resulting in same amino acid change (ClinVar ID: VCV000159226 /PMID: 17106445) and a different missense change at the same codon (p.Ala2436Val / ClinVar ID: VCV001685983)have been previously reported to be associated with NIPBL related disorder.The variant has been previously reported as assumed (i.e. paternity and maternity not confirmed) de novo in at least one similarly affected unrelated individual (PMID: 17106445). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at