rs147054690

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2BP4BS1_SupportingBS2

The NM_133433.4(NIPBL):c.6478G>T(p.Asp2160Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000229 in 1,613,928 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

NIPBL
NM_133433.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:2B:2

Conservation

PhyloP100: 7.64

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 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.

BP4

Computational evidence support a benign effect (MetaRNN=0.3459461).

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000138 (21/152122) while in subpopulation AFR AF= 0.000483 (20/41422). AF 95% confidence interval is 0.00032. There are 0 homozygotes in gnomad4. There are 10 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High AC in GnomAd4 at 21 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NIPBL	NM_133433.4 link	c.6478G>T	p.Asp2160Tyr	missense_variant	Exon 37 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.6478G>T	p.Asp2160Tyr	missense_variant	Exon 37 of 47	1	NM_133433.4	ENSP00000282516.8	Q6KC79-1
NIPBL	ENST00000448238.2 link	c.6478G>T	p.Asp2160Tyr	missense_variant	Exon 37 of 46	1		ENSP00000406266.2	Q6KC79-2
NIPBL	ENST00000652901.1 link	c.6478G>T	p.Asp2160Tyr	missense_variant	Exon 37 of 46			ENSP00000499536.1	A0A590UJS4

Frequencies

GnomAD3 genomes

AF:

0.000138

AC:

AN:

152122

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000483

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:

0.00

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000159

AC:

AN:

251388

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135854

show subpopulations

Gnomad AFR exome

AF:

0.000246

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000109

AC:

AN:

1461806

Hom.:

Cov.:

AF XY:

0.00000963

AC XY:

AN XY:

727208

show subpopulations

Gnomad4 AFR exome

AF:

0.000448

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.000138

AC:

AN:

152122

Hom.:

Cov.:

AF XY:

0.000135

AC XY:

AN XY:

74318

show subpopulations

Gnomad4 AFR

AF:

0.000483

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:

0.00

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.000129

Hom.:

Bravo

AF:

0.000249

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:2Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Cornelia de Lange syndrome 1

Pathogenic:1Uncertain:1

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance: Likely pathogenic

Review Status: flagged submission

Collection Method: clinical testing

- -

Nov 27, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces aspartic acid, which is acidic and polar, with tyrosine, which is neutral and polar, at codon 2160 of the NIPBL protein (p.Asp2160Tyr). This variant is present in population databases (rs147054690, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with NIPBL-related conditions. ClinVar contains an entry for this variant (Variation ID: 159195). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on NIPBL protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not specified

Uncertain:1Benign:1

May 04, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: NIPBL c.6478G>T (p.Asp2160Tyr) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251388 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.6478G>T in individuals affected with Cornelia De Lange Syndrome 1 and no experimental evidence demonstrating its impact on protein function have been reported. Three ClinVar submitters have assessed the variant since 2014: one classified the variant as uncertain significance, one as likely benign, and one as benign. Based on the evidence outlined above, the variant was classified as uncertain significance. -

May 04, 2022

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases

Benign:1

Nov 09, 2022

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Benign

0.0016

BayesDel_noAF

Uncertain

0.040

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.63

D;.

Eigen

Uncertain

0.49

Eigen_PC

Uncertain

0.59

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

D;D

M_CAP

Uncertain

0.15

MetaRNN

Benign

0.35

T;T

MetaSVM

Uncertain

0.61

MutationAssessor

Benign

1.2

L;L

PrimateAI

Uncertain

0.78

PROVEAN

Uncertain

-3.2

D;D

REVEL

Uncertain

0.63

Sift

Uncertain

0.0060

D;D

Sift4G

Uncertain

0.010

D;D

Polyphen

0.74

P;P

Vest4

0.43

MVP

0.85

MPC

1.8

ClinPred

0.85

GERP RS

5.5

Varity_R

0.54

gMVP

0.72

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