chr5-37036347-GTA-G

Variant names:

• chr5-37036347-GTA-G
• rs10554564
• NM_133433.4:c.5863-12_5863-11delAT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_133433.4(NIPBL):​c.5863-12_5863-11delAT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.437 in 371,810 control chromosomes in the GnomAD database, including 22,045 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.51 (17566 hom., cov: 0)
  • Exomes 𝑓: 0.40 (4479 hom.)
• Consequence: NIPBL NM_133433.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.0120
• Publications: 2 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 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: Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP6: Variant 5-37036347-GTA-G is Benign according to our data. Variant chr5-37036347-GTA-G is described in ClinVar as Benign. ClinVar VariationId is 96346.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.622 is higher than 0.05.

Transcripts

RefSeq

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

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NIPBL	ENST00000282516.13	c.5863-31_5863-30delTA		intron_variant	Intron 32 of 46	1	NM_133433.4	ENSP00000282516.8
NIPBL	ENST00000448238.2	c.5863-31_5863-30delTA		intron_variant	Intron 32 of 45	1		ENSP00000406266.2
NIPBL	ENST00000652901.1	c.5863-31_5863-30delTA		intron_variant	Intron 32 of 45			ENSP00000499536.1

Frequencies

GnomAD3 genomes AF: 0.508 AC: 68977 AN: 135742 Hom.: 17560 Cov.: 0

Gnomad AFR AF: 0.629

Gnomad AMI AF: 0.410

Gnomad AMR AF: 0.557

Gnomad ASJ AF: 0.515

Gnomad EAS AF: 0.506

Gnomad SAS AF: 0.526

Gnomad FIN AF: 0.395

Gnomad MID AF: 0.521

Gnomad NFE AF: 0.439

Gnomad OTH AF: 0.522

GnomAD2 exomes AF: 0.476 AC: 15658 AN: 32888 AF XY: 0.472

Gnomad AFR exome AF: 0.526

Gnomad AMR exome AF: 0.492

Gnomad ASJ exome AF: 0.482

Gnomad EAS exome AF: 0.490

Gnomad FIN exome AF: 0.487

Gnomad NFE exome AF: 0.470

Gnomad OTH exome AF: 0.486

GnomAD4 exome AF: 0.396 AC: 93370 AN: 236074 Hom.: 4479 AF XY: 0.400 AC XY: 51694 AN XY: 129076

African (AFR) AF: 0.491 AC: 2126 AN: 4330

American (AMR) AF: 0.470 AC: 2375 AN: 5058

Ashkenazi Jewish (ASJ) AF: 0.437 AC: 2807 AN: 6418

East Asian (EAS) AF: 0.415 AC: 3890 AN: 9374

South Asian (SAS) AF: 0.431 AC: 4275 AN: 9924

European-Finnish (FIN) AF: 0.429 AC: 7419 AN: 17278

Middle Eastern (MID) AF: 0.468 AC: 391 AN: 836

European-Non Finnish (NFE) AF: 0.382 AC: 65766 AN: 172330

Other (OTH) AF: 0.411 AC: 4321 AN: 10526

GnomAD4 genome AF: 0.508 AC: 68991 AN: 135736 Hom.: 17566 Cov.: 0 AF XY: 0.510 AC XY: 33226 AN XY: 65114

African (AFR) AF: 0.629 AC: 23134 AN: 36770

American (AMR) AF: 0.557 AC: 7421 AN: 13312

Ashkenazi Jewish (ASJ) AF: 0.515 AC: 1698 AN: 3300

East Asian (EAS) AF: 0.506 AC: 2384 AN: 4716

South Asian (SAS) AF: 0.527 AC: 2253 AN: 4278

European-Finnish (FIN) AF: 0.395 AC: 2635 AN: 6664

Middle Eastern (MID) AF: 0.534 AC: 143 AN: 268

European-Non Finnish (NFE) AF: 0.439 AC: 28001 AN: 63728

Other (OTH) AF: 0.527 AC: 969 AN: 1838

Alfa AF: 0.271 Hom.: 457

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 05, 2018

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 12, 2015

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.012
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs10554564; hg19: chr5-37036449;