rs727503769

Positions:

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM5PP2BP4_Moderate

The NM_133433.4(NIPBL):c.4321G>A(p.Val1441Ile) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000435 in 1,380,562 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V1441L) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000033 ( 0 hom. )

Consequence

NIPBL
NM_133433.4 missense, splice_region

Scores

Splicing: ADA: 0.7938

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

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 Uncertain_significance. Variant got 1 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr5-37008623-G-T is described in Lovd as [Pathogenic].

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), NIPBL. . Gene score misZ 5.5737 (greater than the threshold 3.09). Trascript score misZ 6.6817 (greater than threshold 3.09). GenCC has associacion of gene with Cornelia de Lange syndrome, Cornelia de Lange syndrome 1.

BP4

Computational evidence support a benign effect (MetaRNN=0.24242437).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NIPBL	NM_133433.4 linkuse as main transcript	c.4321G>A	p.Val1441Ile	missense_variant, splice_region_variant	20/47	ENST00000282516.13	NP_597677.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NIPBL	ENST00000282516.13 linkuse as main transcript	c.4321G>A	p.Val1441Ile	missense_variant, splice_region_variant	20/47	1	NM_133433.4	ENSP00000282516	P1	Q6KC79-1
NIPBL	ENST00000448238.2 linkuse as main transcript	c.4321G>A	p.Val1441Ile	missense_variant, splice_region_variant	20/46	1		ENSP00000406266		Q6KC79-2
NIPBL	ENST00000652901.1 linkuse as main transcript	c.4321G>A	p.Val1441Ile	missense_variant, splice_region_variant	20/46			ENSP00000499536

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

152000

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000400

AC:

AN:

249810

Hom.:

AF XY:

0.00000738

AC XY:

AN XY:

135450

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 SAS exome

AF:

0.0000329

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000326

AC:

AN:

1228562

Hom.:

Cov.:

AF XY:

0.00000321

AC XY:

AN XY:

622976

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000123

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000333

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000132

AC:

AN:

152000

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74238

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.0000294

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 08, 2019

The p.V1441I variant (also known as c.4321G>A) is located in coding exon 19 of the NIPBL gene. The valine at codon 1441 is replaced by isoleucine, an amino acid with highly similar properties. This change occurs in the first base pair of coding exon 19. This amino acid position is highly conserved in available vertebrate species; however, isoleucine is the reference amino acid in other vertebrate species. This variant did not co-segregate with disease in multiple individuals tested in our laboratory (Ambry internal data). Based on four different splice site prediction tools, this alteration is expected to abolish or weaken the native splice acceptor site; however experimental evidence is not currently available. A different alteration located at the same position, p.V1441L (c.4321G>T), has been detected as de novo in three separate individuals: one with classic Cornelia de Lange Syndrome (CdLS), and two others both with mild CdLS phenotypes (Pié J et al. Am. J. Med. Genet. A, 2010 Apr;152A:924-9; Zhong Q et al. Genet Test Mol Biomarkers, 2012 Sep;16:1130-4; Kuzniacka A et al. J. Appl. Genet., 2013 Feb;54:27-33). In addition, the p.V1441I alteration is predicted to be benign and tolerated by PolyPhen and SIFT in silico analyses, respectively. Since supporting evidence is conflicting at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.042

BayesDel_noAF

Benign

-0.20

CADD

Pathogenic

DANN

Benign

0.87

DEOGEN2

Benign

0.13

T;.

Eigen

Benign

-0.045

Eigen_PC

Benign

0.17

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.90

D;D

M_CAP

Benign

0.042

MetaRNN

Benign

0.24

T;T

MetaSVM

Benign

-0.40

MutationAssessor

Benign

0.76

N;N

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.72

PROVEAN

Benign

0.22

N;N

REVEL

Uncertain

0.31

Sift

Benign

0.80

T;T

Sift4G

Benign

0.68

T;T

Polyphen

0.0010

B;B

Vest4

0.27

MutPred

0.35

Gain of catalytic residue at S1443 (P = 0.2022);Gain of catalytic residue at S1443 (P = 0.2022);

MVP

0.72

MPC

0.74

ClinPred

0.38

GERP RS

4.1

Varity_R

0.070

gMVP

0.57

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.79

dbscSNV1_RF

Benign

0.57

SpliceAI score (max)

0.030

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