NM_133433.4:c.3369A>C

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP2BS1_SupportingBS2

The NM_133433.4(NIPBL):c.3369A>C(p.Arg1123Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000143 in 1,613,352 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. R1123R) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

NIPBL
NM_133433.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.99

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 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

PP2

Missense variant in the NIPBL gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 86 curated pathogenic missense variants (we use a threshold of 10). The gene has 69 curated benign missense variants. Gene score misZ: 5.5737 (above the threshold of 3.09). Trascript score misZ: 6.6817 (above the threshold of 3.09). GenCC associations: The gene is linked to Cornelia de Lange syndrome, Cornelia de Lange syndrome 1.

BS1

Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.0000137 (20/1461182) while in subpopulation SAS AF= 0.0000348 (3/86242). AF 95% confidence interval is 0.00000924. There are 0 homozygotes in gnomad4_exome. There are 7 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High AC in GnomAdExome4 at 20 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NIPBL	NM_133433.4 link	c.3369A>C	p.Arg1123Ser	missense_variant	Exon 12 of 47	ENST00000282516.13	NP_597677.2	Q6KC79-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
NIPBL	ENST00000282516.13 link	c.3369A>C	p.Arg1123Ser	missense_variant	Exon 12 of 47	1	NM_133433.4	ENSP00000282516.8	Q6KC79-1
NIPBL	ENST00000448238.2 link	c.3369A>C	p.Arg1123Ser	missense_variant	Exon 12 of 46	1		ENSP00000406266.2	Q6KC79-2
NIPBL	ENST00000652901.1 link	c.3369A>C	p.Arg1123Ser	missense_variant	Exon 12 of 46			ENSP00000499536.1	A0A590UJS4
NIPBL	ENST00000503274.1 link	n.720A>C		non_coding_transcript_exon_variant	Exon 2 of 2	5

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152170

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000159

AC:

AN:

251192

Hom.:

AF XY:

0.00000737

AC XY:

AN XY:

135754

show subpopulations

Gnomad AFR exome

AF:

0.0000616

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000653

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000137

AC:

AN:

1461182

Hom.:

Cov.:

AF XY:

0.00000963

AC XY:

AN XY:

726896

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000144

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152170

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74346

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000302

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Cornelia de Lange syndrome 1

Uncertain:1

Apr 09, 2013

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.82

BayesDel_addAF

Uncertain

0.15

BayesDel_noAF

Pathogenic

0.16

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.27

T;.

Eigen

Uncertain

0.22

Eigen_PC

Uncertain

0.32

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.95

D;D

M_CAP

Uncertain

0.26

MetaRNN

Uncertain

0.47

T;T

MetaSVM

Uncertain

0.64

MutationAssessor

Benign

1.8

L;L

PrimateAI

Uncertain

0.75

PROVEAN

Benign

-1.3

N;N

REVEL

Uncertain

0.56

Sift

Uncertain

0.0020

D;D

Sift4G

Benign

0.31

T;T

Polyphen

0.43

B;D

Vest4

0.54

MutPred

0.31

Gain of phosphorylation at R1123 (P = 4e-04);Gain of phosphorylation at R1123 (P = 4e-04);

MVP

0.88

MPC

1.2

ClinPred

0.20

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.8

Varity_R

0.48

gMVP

0.36

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over