dbSNP rs587783915: NIPBL:p.Pro1035Thr (chr5-36986283-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_133433.4(NIPBL):c.3103C>A(p.Pro1035Thr) 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. 15/22 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. P1035L) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

NIPBL
NM_133433.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.06

Publications

0 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.08917564).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NIPBL	NM_133433.4 link	c.3103C>A	p.Pro1035Thr	missense_variant	Exon 10 of 47	ENST00000282516.13	NP_597677.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
NIPBL	ENST00000282516.13 link	c.3103C>A	p.Pro1035Thr	missense_variant	Exon 10 of 47	1	NM_133433.4	ENSP00000282516.8
NIPBL	ENST00000448238.2 link	c.3103C>A	p.Pro1035Thr	missense_variant	Exon 10 of 46	1		ENSP00000406266.2
NIPBL	ENST00000652901.1 link	c.3103C>A	p.Pro1035Thr	missense_variant	Exon 10 of 46			ENSP00000499536.1
NIPBL	ENST00000504430.5 link	n.2723C>A		non_coding_transcript_exon_variant	Exon 6 of 8	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000581

AC:

AN:

172178

AF XY:

0.0000108

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:

0.0000898

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1363676

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

670894

African (AFR)

AF:

0.00

AC:

AN:

30214

American (AMR)

AF:

0.00

AC:

AN:

28898

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

20490

East Asian (EAS)

AF:

0.00

AC:

AN:

39008

South Asian (SAS)

AF:

0.00

AC:

AN:

68786

European-Finnish (FIN)

AF:

0.00

AC:

AN:

43300

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5234

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1071236

Other (OTH)

AF:

0.00

AC:

AN:

56510

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000831

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.077

BayesDel_addAF

Uncertain

0.047

BayesDel_noAF

Benign

-0.17

CADD

Benign

(source)

DANN

Benign

0.88

DEOGEN2

Benign

0.16

T;.

Eigen

Benign

-0.19

Eigen_PC

Benign

0.022

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.89

D;D

M_CAP

Benign

0.032

MetaRNN

Benign

0.089

T;T

MetaSVM

Uncertain

-0.10

MutationAssessor

Benign

0.69

N;N

PhyloP100

1.1

PrimateAI

Uncertain

0.50

PROVEAN

Benign

-1.0

N;N

REVEL

Benign

0.17

Sift

Benign

0.048

D;T

Sift4G

Benign

0.55

T;T

Polyphen

0.018

B;B

Vest4

0.13

MutPred

0.18

Gain of phosphorylation at P1035 (P = 0.0185);Gain of phosphorylation at P1035 (P = 0.0185);

MVP

0.52

MPC

0.22

ClinPred

0.059

GERP RS

5.2

Varity_R

0.084

gMVP

0.083

Mutation Taster

=90/10

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

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over