Genetic Variant NM_133433.4:c.5863-12_5863-11dupAT (chr5-37036347-G-GTA) – ACMG Classification: Benign (-9 pts)

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6BS1BS2

The NM_133433.4(NIPBL):c.5863-12_5863-11dupAT variant causes a intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0079 ( 6 hom., cov: 0)

Exomes 𝑓: 0.026 ( 0 hom. )

Consequence

NIPBL
NM_133433.4 intron

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 0.0120

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP6

Variant 5-37036347-G-GTA is Benign according to our data. Variant chr5-37036347-G-GTA is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 96347.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00793 (1079/135980) while in subpopulation SAS AF= 0.0175 (75/4284). AF 95% confidence interval is 0.0143. There are 6 homozygotes in gnomad4. There are 498 alleles in male gnomad4 subpopulation. Median coverage is 0. This position pass quality control queck.

BS2

High AC in GnomAd4 at 1079 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NIPBL	NM_133433.4 link	c.5863-12_5863-11dupAT		intron_variant	Intron 32 of 46	ENST00000282516.13	NP_597677.2	Q6KC79-1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
NIPBL	ENST00000282516.13 link	c.5863-32_5863-31insTA	intron_variant	Intron 32 of 46	1	NM_133433.4	ENSP00000282516.8	Q6KC79-1
NIPBL	ENST00000448238.2 link	c.5863-32_5863-31insTA	intron_variant	Intron 32 of 45	1		ENSP00000406266.2	Q6KC79-2
NIPBL	ENST00000652901.1 link	c.5863-32_5863-31insTA	intron_variant	Intron 32 of 45			ENSP00000499536.1	A0A590UJS4

Frequencies

GnomAD3 genomes

AF:

0.00793

AC:

1079

AN:

135986

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0112

Gnomad AMI

AF:

0.00579

Gnomad AMR

AF:

0.00390

Gnomad ASJ

AF:

0.00302

Gnomad EAS

AF:

0.0169

Gnomad SAS

AF:

0.0176

Gnomad FIN

AF:

0.00179

Gnomad MID

AF:

0.00345

Gnomad NFE

AF:

0.00655

Gnomad OTH

AF:

0.00655

GnomAD4 exome

AF:

0.0263

AC:

6378

AN:

242628

Hom.:

Cov.:

AF XY:

0.0278

AC XY:

3686

AN XY:

132528

show subpopulations

Gnomad4 AFR exome

AF:

0.0183

Gnomad4 AMR exome

AF:

0.0171

Gnomad4 ASJ exome

AF:

0.0226

Gnomad4 EAS exome

AF:

0.0270

Gnomad4 SAS exome

AF:

0.0369

Gnomad4 FIN exome

AF:

0.0137

Gnomad4 NFE exome

AF:

0.0277

Gnomad4 OTH exome

AF:

0.0270

GnomAD4 genome

AF:

0.00793

AC:

1079

AN:

135980

Hom.:

Cov.:

AF XY:

0.00763

AC XY:

498

AN XY:

65258

show subpopulations

Gnomad4 AFR

AF:

0.0112

Gnomad4 AMR

AF:

0.00390

Gnomad4 ASJ

AF:

0.00302

Gnomad4 EAS

AF:

0.0169

Gnomad4 SAS

AF:

0.0175

Gnomad4 FIN

AF:

0.00179

Gnomad4 NFE

AF:

0.00655

Gnomad4 OTH

AF:

0.00651

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Jul 15, 2013

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Benign:1

Sep 19, 2017

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over