rs79924167

Positions:

• chr5-37014674-T-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_133433.4(NIPBL):​c.4561-9T>A variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00642 in 1,574,622 control chromosomes in the GnomAD database, including 178 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.020 (82 hom., cov: 32)
  • Exomes 𝑓: 0.0050 (96 hom.)
• Consequence: NIPBL NM_133433.4 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.003446
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 2.47

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 5-37014674-T-A is Benign according to our data. Variant chr5-37014674-T-A is described in ClinVar as [Likely_benign]. Clinvar id is 96342.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-37014674-T-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0601 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NIPBL	NM_133433.4	c.4561-9T>A		splice_polypyrimidine_tract_variant, intron_variant		ENST00000282516.13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NIPBL	ENST00000282516.13	c.4561-9T>A		splice_polypyrimidine_tract_variant, intron_variant		1	NM_133433.4	P1
NIPBL	ENST00000448238.2	c.4561-9T>A		splice_polypyrimidine_tract_variant, intron_variant		1
NIPBL	ENST00000652901.1	c.4561-9T>A		splice_polypyrimidine_tract_variant, intron_variant

Frequencies

GnomAD3 genomes AF: 0.0199 AC: 3024 AN: 152182 Hom.: 82 Cov.: 32

Gnomad AFR AF: 0.0622

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00864

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00931

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.00334

Gnomad OTH AF: 0.0163

GnomAD3 exomes AF: 0.00798 AC: 1997 AN: 250332 Hom.: 40 AF XY: 0.00733 AC XY: 992 AN XY: 135300

Gnomad AFR exome AF: 0.0659

Gnomad AMR exome AF: 0.00541

Gnomad ASJ exome AF: 0.000498

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00833

Gnomad FIN exome AF: 0.0000925

Gnomad NFE exome AF: 0.00397

Gnomad OTH exome AF: 0.00590

GnomAD4 exome AF: 0.00498 AC: 7086 AN: 1422322 Hom.: 96 Cov.: 25 AF XY: 0.00511 AC XY: 3626 AN XY: 710158

Gnomad4 AFR exome AF: 0.0671

Gnomad4 AMR exome AF: 0.00584

Gnomad4 ASJ exome AF: 0.000425

Gnomad4 EAS exome AF: 0.0000254

Gnomad4 SAS exome AF: 0.00922

Gnomad4 FIN exome AF: 0.000131

Gnomad4 NFE exome AF: 0.00303

Gnomad4 OTH exome AF: 0.00757

GnomAD4 genome AF: 0.0199 AC: 3028 AN: 152300 Hom.: 82 Cov.: 32 AF XY: 0.0195 AC XY: 1451 AN XY: 74482

Gnomad4 AFR AF: 0.0621

Gnomad4 AMR AF: 0.00863

Gnomad4 ASJ AF: 0.000864

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00911

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.00334

Gnomad4 OTH AF: 0.0161

Alfa AF: 0.00767 Hom.: 2

Bravo AF: 0.0231

Asia WGS AF: 0.00377 AC: 13 AN: 3466

EpiCase AF: 0.00382

EpiControl AF: 0.00640

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 01, 2019	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 23, 2013	- -

Cornelia de Lange syndrome 1 Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	12
DANN	Benign	0.49

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0034
dbscSNV1_RF	Benign	0.096
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: rs79924167; hg19: chr5-37014776;