rs587783903

chr5-36985631-C-Achr5-36985631-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_133433.4(NIPBL):c.2451C>A(p.Asp817Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,678 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. D817D) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: NIPBL NM_133433.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.914

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 2 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=0.37101078).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NIPBL	NM_133433.4	c.2451C>A	p.Asp817Glu	missense_variant	10/47	ENST00000282516.13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NIPBL	ENST00000282516.13	c.2451C>A	p.Asp817Glu	missense_variant	10/47	1	NM_133433.4	P1
NIPBL	ENST00000448238.2	c.2451C>A	p.Asp817Glu	missense_variant	10/46	1
NIPBL	ENST00000652901.1	c.2451C>A	p.Asp817Glu	missense_variant	10/46
NIPBL	ENST00000504430.5	n.2071C>A		non_coding_transcript_exon_variant	6/8	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461678 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727144

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.060
Cadd	Benign	17
Dann	Uncertain	0.98
DEOGEN2	Benign	0.13	T;.
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.25
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.70	T;T
M_CAP	Benign	0.061	D
MetaRNN	Benign	0.37	T;T
MetaSVM	Uncertain	-0.25	T
MutationAssessor	Benign	0.97	L;L
MutationTaster	Benign	0.70	D;D
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-0.21	N;N
REVEL	Uncertain	0.30
Sift	Pathogenic	0.0	D;D
Sift4G	Benign	0.55	T;T
Polyphen		0.0050	B;B
Vest4		0.59
MutPred		0.12		Gain of MoRF binding (P = 0.1236);Gain of MoRF binding (P = 0.1236);
MVP		0.80
MPC		0.21
ClinPred		0.24	T
GERP RS		3.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.30
gMVP		0.17

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: rs587783903; hg19: chr5-36985733;