rs1669445

Variant names:

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_133433.4(NIPBL):c.3015A>G(p.Leu1005Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00597 in 1,608,350 control chromosomes in the GnomAD database, including 515 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.033 ( 261 hom., cov: 32)

Exomes 𝑓: 0.0032 ( 254 hom. )

Consequence

NIPBL
NM_133433.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 0.123

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 Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.62).

BP6

Variant 5-36986195-A-G is Benign according to our data. Variant chr5-36986195-A-G is described in ClinVar as [Benign]. Clinvar id is 96339.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.123 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.11 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NIPBL	NM_133433.4 link	c.3015A>G	p.Leu1005Leu	synonymous_variant	Exon 10 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.3015A>G	p.Leu1005Leu	synonymous_variant	Exon 10 of 47	1	NM_133433.4	ENSP00000282516.8	Q6KC79-1
NIPBL	ENST00000448238.2 link	c.3015A>G	p.Leu1005Leu	synonymous_variant	Exon 10 of 46	1		ENSP00000406266.2	Q6KC79-2
NIPBL	ENST00000652901.1 link	c.3015A>G	p.Leu1005Leu	synonymous_variant	Exon 10 of 46			ENSP00000499536.1	A0A590UJS4
NIPBL	ENST00000504430.5 link	n.2635A>G		non_coding_transcript_exon_variant	Exon 6 of 8	2

Frequencies

GnomAD3 genomes

AF:

0.0325

AC:

4946

AN:

152128

Hom.:

260

Cov.:

show subpopulations

Gnomad AFR

AF:

0.113

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0138

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000191

Gnomad OTH

AF:

0.0239

GnomAD3 exomes

AF:

0.00860

AC:

2108

AN:

245176

Hom.:

130

AF XY:

0.00616

AC XY:

818

AN XY:

132846

show subpopulations

Gnomad AFR exome

AF:

0.118

Gnomad AMR exome

AF:

0.00544

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000169

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000809

Gnomad OTH exome

AF:

0.00236

GnomAD4 exome

AF:

0.00319

AC:

4648

AN:

1456104

Hom.:

254

Cov.:

AF XY:

0.00266

AC XY:

1925

AN XY:

724196

show subpopulations

Gnomad4 AFR exome

AF:

0.118

Gnomad4 AMR exome

AF:

0.00627

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000223

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000540

Gnomad4 OTH exome

AF:

0.00673

GnomAD4 genome

AF:

0.0325

AC:

4954

AN:

152246

Hom.:

261

Cov.:

AF XY:

0.0314

AC XY:

2337

AN XY:

74436

show subpopulations

Gnomad4 AFR

AF:

0.113

Gnomad4 AMR

AF:

0.0137

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000621

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000191

Gnomad4 OTH

AF:

0.0237

Alfa

AF:

0.0111

Hom.:

Bravo

AF:

0.0380

Asia WGS

AF:

0.00520

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Cornelia de Lange syndrome 1

Benign:5

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Jul 15, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 19, 2013

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 25, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Benign:3

Jun 04, 2014

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 28, 2014

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases

Benign:1

Mar 16, 2016

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as 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. -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.62

CADD

Benign

4.9

DANN

Benign

0.70

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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