5-37051759-ATTTT-ATTTTT

Position:

• chr5-37051759-ATTTT-ATTTTT

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6 BS1 BS2

The NM_133433.4(NIPBL):​c.6955-9dupT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00889 in 1,207,606 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 32)
  • Exomes 𝑓: 0.010 (0 hom.)
• Consequence: NIPBL NM_133433.4 splice_region, intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -0.231

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP6: Variant 5-37051759-A-AT is Benign according to our data. Variant chr5-37051759-A-AT is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1950511.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=1}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.0101 (10704/1058552) while in subpopulation NFE AF= 0.0117 (9335/798608). AF 95% confidence interval is 0.0115. There are 0 homozygotes in gnomad4_exome. There are 5023 alleles in male gnomad4_exome subpopulation. Median coverage is 18. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 27 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NIPBL	NM_133433.4	c.6955-9dupT		splice_region_variant, intron_variant		ENST00000282516.13	NP_597677.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NIPBL	ENST00000282516.13	c.6955-9dupT		splice_region_variant, intron_variant		1	NM_133433.4	ENSP00000282516.8
NIPBL	ENST00000448238.2	c.6955-9dupT		splice_region_variant, intron_variant		1		ENSP00000406266.2
NIPBL	ENST00000652901.1	c.6955-9dupT		splice_region_variant, intron_variant				ENSP00000499536.1
NIPBL	ENST00000514335.1	n.828dupT		non_coding_transcript_exon_variant	1/7	2

Frequencies

GnomAD3 genomes AF: 0.000181 AC: 27 AN: 148962 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000735

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000135

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000586

Gnomad SAS AF: 0.000212

Gnomad FIN AF: 0.000204

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000239

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0101 AC: 10704 AN: 1058552 Hom.: 0 Cov.: 18 AF XY: 0.00948 AC XY: 5023 AN XY: 529704

Gnomad4 AFR exome AF: 0.00849

Gnomad4 AMR exome AF: 0.00457

Gnomad4 ASJ exome AF: 0.00493

Gnomad4 EAS exome AF: 0.00387

Gnomad4 SAS exome AF: 0.00570

Gnomad4 FIN exome AF: 0.00106

Gnomad4 NFE exome AF: 0.0117

Gnomad4 OTH exome AF: 0.00849

GnomAD4 genome AF: 0.000181 AC: 27 AN: 149054 Hom.: 0 Cov.: 32 AF XY: 0.000193 AC XY: 14 AN XY: 72658

Gnomad4 AFR AF: 0.0000733

Gnomad4 AMR AF: 0.000134

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000588

Gnomad4 SAS AF: 0.000213

Gnomad4 FIN AF: 0.000204

Gnomad4 NFE AF: 0.000239

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Orofacial cleft 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Grupo de Genetica Humana, Facultad de Medicina - Universidad de La Sabana

Nov 22, 2022

VUS predicted to be pathogenic by its phyloP score in intron 40 of NIPBL, a gene implicated in morphogenetic processes, development of reproductive structures and sister chromatid cohesion, with a known association with Cornelia de Lange syndrome 1, a condition marked by atypical facial features (such as cleft palate), stunted growth, deformities in the limbs, and cognitive impairment. -

Cornelia de Lange syndrome 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 25, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
La Branchor		0.34
BranchPoint Hunter		4.0

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: rs757731487; hg19: chr5-37051861;