rs80358349
Variant summary
Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_ModerateBP6BP7BS1BS2
The NM_133433.4(NIPBL):c.1212C>T(p.Pro404=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000774 in 1,613,948 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.00045 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000039 ( 0 hom. )
Consequence
NIPBL
NM_133433.4 synonymous
NM_133433.4 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: 1.59
Genes affected
NIPBL (HGNC:28862): (NIPBL cohesin loading factor) This gene encodes the homolog of the Drosophila melanogaster Nipped-B gene product and fungal Scc2-type sister chromatid cohesion proteins. The Drosophila protein facilitates enhancer-promoter communication of remote enhancers and plays a role in developmental regulation. It is also homologous to a family of chromosomal adherins with broad roles in sister chromatid cohesion, chromosome condensation, and DNA repair. The human protein has a bipartite nuclear targeting sequence and a putative HEAT repeat. Condensins, cohesins and other complexes with chromosome-related functions also contain HEAT repeats. Mutations in this gene result in Cornelia de Lange syndrome, a disorder characterized by dysmorphic facial features, growth delay, limb reduction defects, and cognitive disability. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -12 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.4).
BP6
?
Variant 5-36976119-C-T is Benign according to our data. Variant chr5-36976119-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 99919.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Benign=1, Uncertain_significance=1}.
BP7
?
Synonymous conserved (PhyloP=1.59 with no splicing effect.
BS1
?
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000447 (68/152214) while in subpopulation AFR AF= 0.00161 (67/41540). AF 95% confidence interval is 0.0013. There are 0 homozygotes in gnomad4. There are 29 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
?
High AC in GnomAd at 68 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NIPBL | NM_133433.4 | c.1212C>T | p.Pro404= | synonymous_variant | 9/47 | ENST00000282516.13 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NIPBL | ENST00000282516.13 | c.1212C>T | p.Pro404= | synonymous_variant | 9/47 | 1 | NM_133433.4 | P1 | |
NIPBL | ENST00000448238.2 | c.1212C>T | p.Pro404= | synonymous_variant | 9/46 | 1 | |||
NIPBL | ENST00000652901.1 | c.1212C>T | p.Pro404= | synonymous_variant | 9/46 | ||||
NIPBL | ENST00000504430.5 | n.832C>T | non_coding_transcript_exon_variant | 5/8 | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.000447 AC: 68AN: 152096Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000140 AC: 35AN: 250512Hom.: 0 AF XY: 0.0000812 AC XY: 11AN XY: 135464
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GnomAD4 exome AF: 0.0000390 AC: 57AN: 1461734Hom.: 0 Cov.: 32 AF XY: 0.0000316 AC XY: 23AN XY: 727162
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GnomAD4 genome ? AF: 0.000447 AC: 68AN: 152214Hom.: 0 Cov.: 32 AF XY: 0.000390 AC XY: 29AN XY: 74418
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:3
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Cornelia de Lange syndrome 1 Uncertain:1Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Jul 15, 2021 | - - |
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 25, 2024 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Feb 08, 2013 | - - |
not provided Benign:1
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Sep 03, 2020 | - - |
Computational scores
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Name
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BayesDel_noAF
Benign
Cadd
Benign
Dann
Benign
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at