5-36955540-C-T

Variant names:

• chr5-36955540-C-T
• rs80358367
• NM_133433.4:c.133C>T
• NIPBL p.Arg45*

GermlineCancer (beta)

Variant summary

Our verdict is Pathogenic.

+14 Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 14 classification points (ACMG Germline Pathogenicity v2019). PVS1PM2PP5_Strong

The NM_133433.4(NIPBL):c.133C>T (p.Arg45*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant is predicted to lead to nonsense-mediated mRNA decay (NMD). The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. In-silico predictor (BayesDel (noAF)) classifies this variant as likely damaging/oncogenic. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic/Likely Pathogenic (★★). This exact variant is curated in the UniProt human variants database as Uncertain Significance; it is also listed as a COSMIC curated somatic variant.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NIPBL NM_133433.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 3.03
• Publications: 3 publications found

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 Gene-Disease associations (from GenCC):

• Cornelia de Lange syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• Cornelia de Lange syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae)

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Pathogenic. The variant received 14 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PVS1Null variant in LOF gene		Frameshift/stop-gained, NMD predicted, LoF disease mechanism — very strong (PVS1); Stop-gained (exon 3 of 47) at amino acid 45 of 2804, predicted to trigger nonsense-mediated mRNA decay. Loss of function is a known disease mechanism for this gene.
	PM2Absent/extremely low in population databases		Absent from gnomAD (AD/XL gene) — PM2; Absent from gnomAD at well-covered site (MOI: AD/XL) (threshold 0.0001) — PM2 moderate.
	PP5Reputable source reports pathogenic		ClinVar 2-star pathogenic — strong (PP5); ClinVar germline classification: Pathogenic/Likely Pathogenic, 2 star(s).

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_133433.4. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	NIPBL NM_133433.4	MANE Select	c.133C>T p.Arg45*	stop_gained	Exon 3 of 47	Prot: NP_597677.2
	NIPBL NM_001438586.1		c.133C>T p.Arg45*	stop_gained	Exon 3 of 47	Prot: NP_001425515.1
	NIPBL NM_015384.5		c.133C>T p.Arg45*	stop_gained	Exon 3 of 46	Prot: NP_056199.2

NIPBL NM_133433.4

MANE Select

HGVSc / HGVSpc.133C>Tp.Arg45*

Exon rankExon 3 of 47

stop_gained

Prot: NP_597677.2

NIPBL NM_001438586.1

HGVSc / HGVSpc.133C>Tp.Arg45*

Exon rankExon 3 of 47

stop_gained

Prot: NP_001425515.1

NIPBL NM_015384.5

HGVSc / HGVSpc.133C>Tp.Arg45*

Exon rankExon 3 of 46

stop_gained

Prot: NP_056199.2

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	NIPBL ENST00000282516.13	TSL:1MANE Select	c.133C>T p.Arg45*	stop_gained	Exon 3 of 47	Prot: ENSP00000282516.8 UniProt:
	NIPBL ENST00000448238.2	TSL:1	c.133C>T p.Arg45*	stop_gained	Exon 3 of 46	Prot: ENSP00000406266.2 UniProt:
	NIPBL ENST00000652901.1		c.133C>T p.Arg45*	stop_gained	Exon 3 of 46	Prot: ENSP00000499536.1 UniProt:

NIPBL ENST00000282516.13

TSL:1MANE Select

HGVSc / HGVSpc.133C>Tp.Arg45*

Exon rankExon 3 of 47

stop_gained

Prot: ENSP00000282516.8UniProt: Q6KC79-1

NIPBL ENST00000448238.2

TSL:1

HGVSc / HGVSpc.133C>Tp.Arg45*

Exon rankExon 3 of 46

stop_gained

Prot: ENSP00000406266.2UniProt: Q6KC79-2

NIPBL ENST00000652901.1

HGVSc / HGVSpc.133C>Tp.Arg45*

Exon rankExon 3 of 46

stop_gained

Prot: ENSP00000499536.1UniProt: A0A590UJS4

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 4 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:32
GnomAD4 exome	AF:	AC:	Hom:	AN:	Cov:31
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.00000490	AC:1	Hom:0	AN:204266	Cov:

Showing 4 sources

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	Cornelia de Lange syndrome 1 (3)
2	-	-	not provided (2)
1	-	-	NIPBL-related disorder (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	35
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	36
DANN	Uncertain	1.0
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.87	D
GPN-Star LLR	N/A	-10
GPN-Star score	N/A	10
Mutation Taster	N/A	0/200	disease causing (ClinVar)
PhyloP100	Benign	3.0

Showing 12 of 12 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.0
SpliceAI score (max)	Benign	0.010	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs80358367;

hg19: chr5-36955642;

COSMIC: COSV56963663;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar