5-37048525-A-G
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Variant summary
Our verdict is Benign. Variant got -11 ACMG points: 3P and 14B. PM1PP2BP4_ModerateBP6_Very_StrongBS2
The NM_133433.4(NIPBL):āc.6613A>Gā(p.Ser2205Gly) variant causes a missense change. The variant allele was found at a frequency of 0.0000164 in 1,583,802 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (ā ā ).
Frequency
Genomes: š 0.000026 ( 0 hom., cov: 32)
Exomes š: 0.000015 ( 0 hom. )
Consequence
NIPBL
NM_133433.4 missense
NM_133433.4 missense
Scores
3
16
Clinical Significance
Conservation
PhyloP100: 4.77
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 -11 ACMG points.
PM1
In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in NM_133433.4
PP2
Missense variant where missense usually causes diseases, NIPBL
BP4
Computational evidence support a benign effect (MetaRNN=0.08151165).
BP6
Variant 5-37048525-A-G is Benign according to our data. Variant chr5-37048525-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 159203.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS2
High AC in GnomAdExome4 at 22 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NIPBL | NM_133433.4 | c.6613A>G | p.Ser2205Gly | missense_variant | 39/47 | ENST00000282516.13 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NIPBL | ENST00000282516.13 | c.6613A>G | p.Ser2205Gly | missense_variant | 39/47 | 1 | NM_133433.4 | P1 | |
NIPBL | ENST00000448238.2 | c.6613A>G | p.Ser2205Gly | missense_variant | 39/46 | 1 | |||
NIPBL | ENST00000652901.1 | c.6613A>G | p.Ser2205Gly | missense_variant | 39/46 |
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152012Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000912 AC: 22AN: 241258Hom.: 0 AF XY: 0.0000382 AC XY: 5AN XY: 130882
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GnomAD4 exome AF: 0.0000154 AC: 22AN: 1431790Hom.: 0 Cov.: 29 AF XY: 0.00000703 AC XY: 5AN XY: 711130
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GnomAD4 genome AF: 0.0000263 AC: 4AN: 152012Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3AN XY: 74248
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ClinVar
Significance: Likely benign
Submissions summary: Benign:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Cornelia de Lange syndrome 1 Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Dec 11, 2023 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Jul 15, 2021 | - - |
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Feb 08, 2013 | - - |
Inborn genetic diseases Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 09, 2021 | 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
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
DEOGEN2
Benign
T;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D
M_CAP
Benign
T
MetaRNN
Benign
T;T
MetaSVM
Benign
T
MutationAssessor
Benign
N;N
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N
REVEL
Benign
Sift
Benign
T;T
Sift4G
Benign
T;T
Polyphen
B;B
Vest4
MutPred
Loss of helix (P = 0.2662);Loss of helix (P = 0.2662);
MVP
MPC
ClinPred
T
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Varity_R
gMVP
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