Genetic Variant NIPBL:p.Ile1982Val (chr5-37036460-A-G) – 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.5944A>G(p.Ile1982Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000766 in 1,306,164 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 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. I1982L) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 30)

Exomes 𝑓: 7.7e-7 ( 0 hom. )

Consequence

NIPBL
NM_133433.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 8.94

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:

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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=0.22717896).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NIPBL	NM_133433.4 link	c.5944A>G	p.Ile1982Val	missense_variant	Exon 33 of 47	ENST00000282516.13	NP_597677.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
NIPBL	ENST00000282516.13 link	c.5944A>G	p.Ile1982Val	missense_variant	Exon 33 of 47	1	NM_133433.4	ENSP00000282516.8
NIPBL	ENST00000448238.2 link	c.5944A>G	p.Ile1982Val	missense_variant	Exon 33 of 46	1		ENSP00000406266.2
NIPBL	ENST00000652901.1 link	c.5944A>G	p.Ile1982Val	missense_variant	Exon 33 of 46			ENSP00000499536.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.66e-7

AC:

AN:

1306164

Hom.:

Cov.:

AF XY:

0.00000155

AC XY:

AN XY:

645004

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

29236

American (AMR)

AF:

0.00

AC:

AN:

32734

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23364

East Asian (EAS)

AF:

0.00

AC:

AN:

33452

South Asian (SAS)

AF:

0.00

AC:

AN:

64742

European-Finnish (FIN)

AF:

0.00

AC:

AN:

45384

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3752

European-Non Finnish (NFE)

AF:

9.80e-7

AC:

AN:

1020184

Other (OTH)

AF:

0.00

AC:

AN:

53316

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.0022

BayesDel_noAF

Benign

-0.24

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.14

T;.

Eigen

Benign

-0.048

Eigen_PC

Benign

0.19

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.94

D;D

M_CAP

Benign

0.028

MetaRNN

Benign

0.23

T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

0.47

N;N

PhyloP100

8.9

PrimateAI

Pathogenic

0.85

PROVEAN

Benign

0.060

N;N

REVEL

Benign

0.21

Sift

Benign

0.27

T;T

Sift4G

Benign

0.93

T;T

Vest4

0.54

ClinPred

0.76

GERP RS

5.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.14

gMVP

0.22

Mutation Taster

=77/23

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