Genetic Variant NM_133433.4:c.133_135delCGAinsGGG (chr5-36955540-CGA-GGG) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is The variant received 2 classification points (ACMG Germline Pathogenicity v2019). PM2

The NM_133433.4(NIPBL):c.133_135delCGAinsGGG (p.Arg45Gly) variant causes a missense change. 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 ACMG Germline Pathogenicity v2019

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
	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.

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_135delCGAinsGGG p.Arg45Gly	missense	N/A	Prot: NP_597677.2
NIPBL NM_001438586.1		c.133_135delCGAinsGGG p.Arg45Gly	missense	N/A	Prot: NP_001425515.1
NIPBL NM_015384.5		c.133_135delCGAinsGGG p.Arg45Gly	missense	N/A	Prot: NP_056199.2

NIPBL NM_133433.4

MANE Select

HGVSc / HGVSpc.133_135delCGAinsGGGp.Arg45Gly

Exon rankN/A

missense

Prot: NP_597677.2

NIPBL NM_001438586.1

HGVSc / HGVSpc.133_135delCGAinsGGGp.Arg45Gly

Exon rankN/A

missense

Prot: NP_001425515.1

NIPBL NM_015384.5

HGVSc / HGVSpc.133_135delCGAinsGGGp.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_135delCGAinsGGG p.Arg45Gly	missense	N/A	Prot: ENSP00000282516.8 UniProt: Q6KC79-1
NIPBL ENST00000448238.2	TSL:1	c.133_135delCGAinsGGG p.Arg45Gly	missense	N/A	Prot: ENSP00000406266.2 UniProt: Q6KC79-2
NIPBL ENST00000652901.1		c.133_135delCGAinsGGG p.Arg45Gly	missense	N/A	Prot: ENSP00000499536.1 UniProt: A0A590UJS4

NIPBL ENST00000282516.13

TSL:1MANE Select

HGVSc / HGVSpc.133_135delCGAinsGGGp.Arg45Gly

Exon rankN/A

missense

Prot: ENSP00000282516.8UniProt: Q6KC79-1

NIPBL ENST00000448238.2

TSL:1

HGVSc / HGVSpc.133_135delCGAinsGGGp.Arg45Gly

Exon rankN/A

missense

Prot: ENSP00000406266.2UniProt: Q6KC79-2

NIPBL ENST00000652901.1

HGVSc / HGVSpc.133_135delCGAinsGGGp.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 ACMG Germline Pathogenicity v2019

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