rs1345465032

Variant names:

• chr5-36876842-CT-C
• rs1345465032
• NM_133433.4:c.-415delT

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_133433.4(NIPBL):​c.-415delT variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. There is a variant allele frequency bias in the population database for this variant (GnomAd4), which may indicate mosaicism or somatic mutations in the reference population data. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00026 (0 hom., cov: 0)
  • Exomes 𝑓: 0.00033 (0 hom.)
• Consequence: NIPBL NM_133433.4 5_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.288
• Publications: 0 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-DT (HGNC:51293): (NIPBL divergent transcript)

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NIPBL	NM_133433.4	c.-415delT		5_prime_UTR_variant	Exon 1 of 47	ENST00000282516.13	NP_597677.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NIPBL	ENST00000282516.13	c.-415delT		5_prime_UTR_variant	Exon 1 of 47	1	NM_133433.4	ENSP00000282516.8

Frequencies

GnomAD3 genomes AF: 0.000257 AC: 38 AN: 147726 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000150

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000200

Gnomad ASJ AF: 0.000294

Gnomad EAS AF: 0.00123

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.000257

Gnomad OTH AF: 0.00200

GnomAD4 exome AF: 0.000329 AC: 79 AN: 240480 Hom.: 0 Cov.: 0 AF XY: 0.000393 AC XY: 48 AN XY: 122236

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000146 AC: 1 AN: 6872

American (AMR) AF: 0.000416 AC: 3 AN: 7212

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 8910

East Asian (EAS) AF: 0.00175 AC: 39 AN: 22304

South Asian (SAS) AF: 0.00 AC: 0 AN: 2978

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 20688

Middle Eastern (MID) AF: 0.000796 AC: 1 AN: 1256

European-Non Finnish (NFE) AF: 0.000201 AC: 31 AN: 154374

Other (OTH) AF: 0.000252 AC: 4 AN: 15886

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.000257 AC: 38 AN: 147818 Hom.: 0 Cov.: 0 AF XY: 0.000194 AC XY: 14 AN XY: 72096

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000149 AC: 6 AN: 40188

American (AMR) AF: 0.000200 AC: 3 AN: 14990

Ashkenazi Jewish (ASJ) AF: 0.000294 AC: 1 AN: 3396

East Asian (EAS) AF: 0.00123 AC: 6 AN: 4870

South Asian (SAS) AF: 0.00 AC: 0 AN: 4470

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10436

Middle Eastern (MID) AF: 0.00342 AC: 1 AN: 292

European-Non Finnish (NFE) AF: 0.000257 AC: 17 AN: 66256

Other (OTH) AF: 0.00198 AC: 4 AN: 2024

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jan 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NIPBL: BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.29

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

Other links and lift over

dbSNP: rs1345465032; hg19: chr5-36876944;