rs121918264

Variant summary

Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PVS1PS1_ModeratePM2PP5_Very_Strong

The ENST00000282516.13(NIPBL):​c.2T>A​(p.Met1?) variant causes a start lost 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 (★★).

Frequency

Genomes: not found (cov: 32)

Consequence

NIPBL
ENST00000282516.13 start_lost

Scores

11
2
3

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 7.60
Variant links:
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 Pathogenic. Variant got 20 ACMG points.

PVS1
Start lost variant, no new inframe start found.
PS1
Another start lost variant in ENST00000282516.13 (NIPBL) was described as [Pathogenic] in ClinVar as 159103
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 5-36953698-T-A is Pathogenic according to our data. Variant chr5-36953698-T-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2139.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-36953698-T-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
NIPBLNM_133433.4 linkuse as main transcriptc.2T>A p.Met1? start_lost 2/47 ENST00000282516.13 NP_597677.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
NIPBLENST00000282516.13 linkuse as main transcriptc.2T>A p.Met1? start_lost 2/471 NM_133433.4 ENSP00000282516 P1Q6KC79-1
NIPBLENST00000448238.2 linkuse as main transcriptc.2T>A p.Met1? start_lost 2/461 ENSP00000406266 Q6KC79-2
NIPBLENST00000652901.1 linkuse as main transcriptc.2T>A p.Met1? start_lost 2/46 ENSP00000499536

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
30
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Cornelia de Lange syndrome 1 Pathogenic:2
Pathogenic, no assertion criteria providedliterature onlyOMIMJun 01, 2004- -
Likely pathogenic, criteria provided, single submitterclinical testing3billionSep 01, 2022The variant is not observed in the gnomAD v2.1.1 dataset. Start lost variant. The variant has been reported to be associated with NIPBL -related disorder (ClinVar ID: VCV000002139 / PMID: 15146186). However, the evidence of pathogenicity is insufficient at this time. Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline. -
not provided Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingGeneDxFeb 05, 2024Initiation codon variant in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26147798, 22581668, 24038889, 15146186) -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.63
D
BayesDel_noAF
Pathogenic
0.58
CADD
Pathogenic
28
DANN
Uncertain
0.99
DEOGEN2
Benign
0.37
T;.
Eigen
Pathogenic
0.69
Eigen_PC
Pathogenic
0.71
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.90
D;D
M_CAP
Pathogenic
0.93
D
MetaRNN
Pathogenic
0.99
D;D
MetaSVM
Pathogenic
1.1
D
MutationTaster
Benign
1.0
A;A
PROVEAN
Benign
-1.6
N;N
REVEL
Pathogenic
0.87
Sift
Pathogenic
0.0
D;D
Sift4G
Pathogenic
0.0
D;D
Polyphen
0.93
P;D
Vest4
0.96
MutPred
0.98
Loss of stability (P = 0.0059);Loss of stability (P = 0.0059);
MVP
0.99
ClinPred
0.99
D
GERP RS
5.6
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.90
gMVP
0.91

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs121918264; hg19: chr5-36953800; COSMIC: COSV56950018; COSMIC: COSV56950018; API