rs1554032789

Variant names:

• chr5-37048547-T-A
• rs1554032789
• NM_133433.4:c.6635T>A

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP2 PP3_Moderate PP5_Moderate

The NM_133433.4(NIPBL):​c.6635T>A​(p.Val2212Glu) variant causes a missense change involving the alteration of a 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 Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: NIPBL NM_133433.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.65

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 Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the NIPBL gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 86 curated pathogenic missense variants (we use a threshold of 10). The gene has 69 curated benign missense variants. Gene score misZ: 5.5737 (above the threshold of 3.09). Trascript score misZ: 6.6817 (above the threshold of 3.09). GenCC associations: The gene is linked to Cornelia de Lange syndrome, Cornelia de Lange syndrome 1.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.907
• PP5: Variant 5-37048547-T-A is Pathogenic according to our data. Variant chr5-37048547-T-A is described in ClinVar as [Pathogenic]. Clinvar id is 446367.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NIPBL	NM_133433.4	c.6635T>A	p.Val2212Glu	missense_variant	Exon 39 of 47	ENST00000282516.13	NP_597677.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NIPBL	ENST00000282516.13	c.6635T>A	p.Val2212Glu	missense_variant	Exon 39 of 47	1	NM_133433.4	ENSP00000282516.8
NIPBL	ENST00000448238.2	c.6635T>A	p.Val2212Glu	missense_variant	Exon 39 of 46	1		ENSP00000406266.2
NIPBL	ENST00000652901.1	c.6635T>A	p.Val2212Glu	missense_variant	Exon 39 of 46			ENSP00000499536.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Cornelia de Lange syndrome 1 Pathogenic:1

Sep 22, 2017

Department Of Genetics, Lifeline Super Speciality Hospital, Adoor.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.47
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.80	D;.
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D;D
M_CAP	Pathogenic	0.72	D
MetaRNN	Pathogenic	0.91	D;D
MetaSVM	Pathogenic	0.94	D
MutationAssessor	Uncertain	2.2	M;M
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-4.1	D;D
REVEL	Pathogenic	0.94
Sift	Uncertain	0.0030	D;D
Sift4G	Uncertain	0.0040	D;D
Polyphen		0.99	D;D
Vest4		0.95
MutPred		0.65		Gain of disorder (P = 0.004);Gain of disorder (P = 0.004);
MVP		0.99
MPC		2.5
ClinPred		0.98	D
GERP RS		6.1
Varity_R		0.91
gMVP		0.96

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: rs1554032789; hg19: chr5-37048649;