Genetic Variant NIPBL:p.Arg45Gly (chr5-36955540-CGA-GGT) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is The variant received 2 classification points (ACGS-UK Somatic Oncogenicity v2025). O3_Moderate

The NM_133433.4(NIPBL):c.133_135delCGAinsGGT (p.Arg45Gly) variant causes a missense change. The gene NIPBL is a tumor suppressor gene (CancerMine: 1 TSG citations). Note: allele frequency estimates from gnomAD may be inaccurate for this variant type (MNP or indel longer than 3 bp) due to technology limitations. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. The affected nucleotide is highly conserved across species (PhyloP 100-way vertebrate score: 9.54). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.R45Q: Uncertain_significance (ClinVar VariationId 1918803, 1 star)

Frequency

Genomes: not found (cov: 32)

Consequence

NIPBL
NM_133433.4 missense

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 9.54

Publications

0 publications found

Variant links:

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)

NIPBL links:

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new If you want to explore the variant's impact on the transcript NM_133433.4, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

Classification according to ACGS-UK Somatic Oncogenicity v2025

Classification was made for transcript:

Our verdict: Uncertain_significance. The variant received 2 points.

Show applied only (1)

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	O3Absent or very rare in population		Absent or extremely rare in gnomAD (AC ≤ 2) — O3 moderate; GnomAD: AF = absent, AC = 0 — absent/extremely rare (O3 moderate [+2])

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

Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
NIPBL NM_133433.4	MANE Select	c.133_135delCGAinsGGT p.Arg45Gly	missense	N/A	Prot: NP_597677.2
NIPBL NM_001438586.1		c.133_135delCGAinsGGT p.Arg45Gly	missense	N/A	Prot: NP_001425515.1
NIPBL NM_015384.5		c.133_135delCGAinsGGT p.Arg45Gly	missense	N/A	Prot: NP_056199.2

NIPBL NM_133433.4

MANE Select

HGVSc / HGVSpc.133_135delCGAinsGGTp.Arg45Gly

Exon rankN/A

missense

Prot: NP_597677.2

NIPBL NM_001438586.1

HGVSc / HGVSpc.133_135delCGAinsGGTp.Arg45Gly

Exon rankN/A

missense

Prot: NP_001425515.1

NIPBL NM_015384.5

HGVSc / HGVSpc.133_135delCGAinsGGTp.Arg45Gly

Exon rankN/A

missense

Prot: NP_056199.2

Ensembl Transcripts

Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
NIPBL ENST00000282516.13	TSL:1MANE Select	c.133_135delCGAinsGGT p.Arg45Gly	missense	N/A	Prot: ENSP00000282516.8 UniProt: Q6KC79-1
NIPBL ENST00000448238.2	TSL:1	c.133_135delCGAinsGGT p.Arg45Gly	missense	N/A	Prot: ENSP00000406266.2 UniProt: Q6KC79-2
NIPBL ENST00000652901.1		c.133_135delCGAinsGGT p.Arg45Gly	missense	N/A	Prot: ENSP00000499536.1 UniProt: A0A590UJS4

NIPBL ENST00000282516.13

TSL:1MANE Select

HGVSc / HGVSpc.133_135delCGAinsGGTp.Arg45Gly

Exon rankN/A

missense

Prot: ENSP00000282516.8UniProt: Q6KC79-1

NIPBL ENST00000448238.2

TSL:1

HGVSc / HGVSpc.133_135delCGAinsGGTp.Arg45Gly

Exon rankN/A

missense

Prot: ENSP00000406266.2UniProt: Q6KC79-2

NIPBL ENST00000652901.1

HGVSc / HGVSpc.133_135delCGAinsGGTp.Arg45Gly

Exon rankN/A

missense

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 2 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:32
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32

Showing 2 sources

Tested, but no data found:GnomAD4 exomeIf GnomAD4 is missing, the position is probably not covered by the project.

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
PhyloP100	Pathogenic	9.5

Showing 1 of 1 scores

Splicing Scores

No splicing scores have been computed for this variant.

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.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

Classification according to ACGS-UK Somatic Oncogenicity v2025

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational Scores

Splicing Scores

MaveDB functional evidence ?

Publications

Other links and lift over

MaveDB functional evidence