rs138440449
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Variant summary
Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2
The NM_133433.4(NIPBL):āc.4245A>Cā(p.Ser1415=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000403 in 1,600,804 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (ā ā ).
Frequency
Genomes: š 0.0021 ( 0 hom., cov: 32)
Exomes š: 0.00022 ( 2 hom. )
Consequence
NIPBL
NM_133433.4 synonymous
NM_133433.4 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: -0.0640
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 -21 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.49).
BP6
?
Variant 5-37008013-A-C is Benign according to our data. Variant chr5-37008013-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 476590.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-37008013-A-C is described in Lovd as [Likely_benign].
BP7
?
Synonymous conserved (PhyloP=-0.064 with no splicing effect.
BS1
?
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00212 (322/152230) while in subpopulation AFR AF= 0.00738 (307/41584). AF 95% confidence interval is 0.0067. There are 0 homozygotes in gnomad4. There are 143 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
?
High AC in GnomAd4 at 322 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NIPBL | NM_133433.4 | c.4245A>C | p.Ser1415= | synonymous_variant | 19/47 | ENST00000282516.13 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NIPBL | ENST00000282516.13 | c.4245A>C | p.Ser1415= | synonymous_variant | 19/47 | 1 | NM_133433.4 | P1 | |
NIPBL | ENST00000448238.2 | c.4245A>C | p.Ser1415= | synonymous_variant | 19/46 | 1 | |||
NIPBL | ENST00000652901.1 | c.4245A>C | p.Ser1415= | synonymous_variant | 19/46 |
Frequencies
GnomAD3 genomes ? AF: 0.00212 AC: 323AN: 152112Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000558 AC: 140AN: 250936Hom.: 0 AF XY: 0.000413 AC XY: 56AN XY: 135682
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GnomAD4 exome AF: 0.000223 AC: 323AN: 1448574Hom.: 2 Cov.: 28 AF XY: 0.000212 AC XY: 153AN XY: 721718
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GnomAD4 genome ? AF: 0.00212 AC: 322AN: 152230Hom.: 0 Cov.: 32 AF XY: 0.00192 AC XY: 143AN XY: 74440
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Benign:3
Benign, criteria provided, single submitter | clinical testing | GeneDx | Aug 24, 2021 | - - |
Benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Sep 01, 2022 | NIPBL: BS1, BS2 - |
Benign, criteria provided, single submitter | clinical testing | Athena Diagnostics | Nov 28, 2018 | - - |
Cornelia de Lange syndrome 1 Benign:2
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 22, 2024 | - - |
Benign, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Jul 15, 2021 | - - |
Inborn genetic diseases Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 11, 2016 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Computational scores
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Name
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
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