rs80358365

Positions:

• chr5-36985772-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 3P and 3B. PM2 PP2 BP4_Moderate BP6

The NM_133433.4(NIPBL):​c.2592T>A​(p.Asp864Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,640 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: NIPBL NM_133433.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 0.125

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, NIPBL
• BP4: Computational evidence support a benign effect (MetaRNN=0.16518724).
• BP6: Variant 5-36985772-T-A is Benign according to our data. Variant chr5-36985772-T-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 99925.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NIPBL	NM_133433.4	c.2592T>A	p.Asp864Glu	missense_variant	10/47	ENST00000282516.13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NIPBL	ENST00000282516.13	c.2592T>A	p.Asp864Glu	missense_variant	10/47	1	NM_133433.4	P1
NIPBL	ENST00000448238.2	c.2592T>A	p.Asp864Glu	missense_variant	10/46	1
NIPBL	ENST00000652901.1	c.2592T>A	p.Asp864Glu	missense_variant	10/46
NIPBL	ENST00000504430.5	n.2212T>A		non_coding_transcript_exon_variant	6/8	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461640 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 727112

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Cornelia de Lange syndrome 1 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Feb 08, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	11
DANN	Benign	0.96
DEOGEN2	Benign	0.081	T;.
Eigen	Benign	-0.65
Eigen_PC	Benign	-0.44
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.70	T;T
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.17	T;T
MetaSVM	Benign	-0.57	T
MutationAssessor	Benign	0.0	N;N
MutationTaster	Benign	0.033	A;A
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-0.020	N;N
REVEL	Benign	0.17
Sift	Benign	0.56	T;T
Sift4G	Benign	0.98	T;T
Polyphen		0.0	B;B
Vest4		0.041
MutPred		0.18		Gain of solvent accessibility (P = 0.0306);Gain of solvent accessibility (P = 0.0306);
MVP		0.39
MPC		0.18
ClinPred		0.083	T
GERP RS		2.2
Varity_R		0.033
gMVP		0.064

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: rs80358365; hg19: chr5-36985874;