dbSNP rs16903425: NIPBL:p.Ser261Thr (chr5-36971954-T-A) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_133433.4(NIPBL):c.781T>A(p.Ser261Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S261A) has been classified as Benign.

Frequency

Genomes: not found (cov: 32)

Consequence

NIPBL
NM_133433.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.69

Publications

8 publications found

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]

NIPBL Gene-Disease associations (from GenCC):

Cornelia de Lange syndrome
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
Cornelia de Lange syndrome 1
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P

NIPBL links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.31055224).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_133433.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
NIPBL	NM_133433.4	MANE Select	c.781T>A	p.Ser261Thr	missense	Exon 8 of 47	NP_597677.2
NIPBL	NM_001438586.1		c.781T>A	p.Ser261Thr	missense	Exon 8 of 47	NP_001425515.1
NIPBL	NM_015384.5		c.781T>A	p.Ser261Thr	missense	Exon 8 of 46	NP_056199.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
NIPBL	ENST00000282516.13	TSL:1 MANE Select	c.781T>A	p.Ser261Thr	missense	Exon 8 of 47	ENSP00000282516.8
NIPBL	ENST00000448238.2	TSL:1	c.781T>A	p.Ser261Thr	missense	Exon 8 of 46	ENSP00000406266.2
NIPBL	ENST00000652901.1		c.781T>A	p.Ser261Thr	missense	Exon 8 of 46	ENSP00000499536.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

250974

AF XY:

0.00000737

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000882

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.081

BayesDel_addAF

Uncertain

0.095

BayesDel_noAF

Benign

-0.10

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.14

Eigen

Benign

-0.30

Eigen_PC

Benign

-0.075

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.72

M_CAP

Benign

0.071

MetaRNN

Benign

0.31

MetaSVM

Uncertain

-0.026

MutationAssessor

Benign

1.4

PhyloP100

1.7

PrimateAI

Benign

0.46

PROVEAN

Benign

-0.42

REVEL

Uncertain

0.31

Sift

Uncertain

0.0070

Sift4G

Benign

0.20

Polyphen

0.083

Vest4

0.40

MutPred

0.11

Gain of helix (P = 0.0093)

MVP

0.76

MPC

0.21

ClinPred

0.57

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.13

gMVP

0.35

Mutation Taster

=99/1

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over