rs80358373

Positions:

• chr5-37022382-A-G

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Moderate

The NM_133433.4(NIPBL):​c.5566A>G​(p.Arg1856Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1856T) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: NIPBL NM_133433.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 2.01

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]

ACMG classification

Verdict is Pathogenic. Variant got 13 ACMG points.

• PM1: In a repeat HEAT 2 (size 38) in uniprot entity NIPBL_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_133433.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
• 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). The gene has 86 curated pathogenic missense variants (we use a threshold of 10). The gene has 69 curated benign missense variants. GenCC has associacion of the gene with Cornelia de Lange syndrome, Cornelia de Lange syndrome 1.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.976
• PP5: Variant 5-37022382-A-G is Pathogenic according to our data. Variant chr5-37022382-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 99934.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-37022382-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NIPBL	NM_133433.4	c.5566A>G	p.Arg1856Gly	missense_variant	29/47	ENST00000282516.13	NP_597677.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NIPBL	ENST00000282516.13	c.5566A>G	p.Arg1856Gly	missense_variant	29/47	1	NM_133433.4	ENSP00000282516.8
NIPBL	ENST00000448238.2	c.5566A>G	p.Arg1856Gly	missense_variant	29/46	1		ENSP00000406266.2
NIPBL	ENST00000652901.1	c.5566A>G	p.Arg1856Gly	missense_variant	29/46			ENSP00000499536.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Cornelia de Lange syndrome 1 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Feb 08, 2013

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.23
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.86	D;.
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Pathogenic	0.56	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Uncertain	0.21	D
MutationAssessor	Pathogenic	3.4	M;M
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-6.6	D;D
REVEL	Pathogenic	0.68
Sift	Uncertain	0.021	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.99
MutPred		0.84		Loss of stability (P = 0.0104);Loss of stability (P = 0.0104);
MVP		0.98
MPC		2.3
ClinPred		0.99	D
GERP RS		2.4
Varity_R		0.90
gMVP		0.95

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

Other links and lift over

dbSNP: rs80358373; hg19: chr5-37022484;