5-36877098-A-AC

Variant names:

• chr5-36877098-A-AC
• rs567891305
• NM_133433.4:c.-153dupC

Variant summary

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

The NM_133433.4(NIPBL):​c.-153dupC variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000783 in 319,110 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.000056 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000097 (0 hom.)
• Consequence: NIPBL NM_133433.4 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.16
• 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 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: 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.-153dupC		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.-153dupC		5_prime_UTR_variant	Exon 1 of 47	1	NM_133433.4	ENSP00000282516.8
NIPBL	ENST00000448238.2	c.-153dupC		5_prime_UTR_variant	Exon 1 of 46	1		ENSP00000406266.2
NIPBL	ENST00000652901.1	c.-153dupC		5_prime_UTR_variant	Exon 1 of 46			ENSP00000499536.1

Frequencies

GnomAD3 genomes AF: 0.0000487 AC: 7 AN: 143716 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000775

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000213

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000105

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000306

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000970 AC: 17 AN: 175284 Hom.: 0 Cov.: 0 AF XY: 0.0000778 AC XY: 7 AN XY: 90010

African (AFR) AF: 0.00 AC: 0 AN: 4934

American (AMR) AF: 0.00 AC: 0 AN: 5240

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 6442

East Asian (EAS) AF: 0.00 AC: 0 AN: 15040

South Asian (SAS) AF: 0.00 AC: 0 AN: 1604

European-Finnish (FIN) AF: 0.000495 AC: 8 AN: 16152

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 890

European-Non Finnish (NFE) AF: 0.0000705 AC: 8 AN: 113484

Other (OTH) AF: 0.0000870 AC: 1 AN: 11498

GnomAD4 genome AF: 0.0000556 AC: 8 AN: 143826 Hom.: 0 Cov.: 31 AF XY: 0.0000713 AC XY: 5 AN XY: 70090

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

African (AFR) AF: 0.0000772 AC: 3 AN: 38850

American (AMR) AF: 0.00 AC: 0 AN: 14670

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3350

East Asian (EAS) AF: 0.000214 AC: 1 AN: 4678

South Asian (SAS) AF: 0.00 AC: 0 AN: 4294

European-Finnish (FIN) AF: 0.000105 AC: 1 AN: 9524

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 272

European-Non Finnish (NFE) AF: 0.0000306 AC: 2 AN: 65310

Other (OTH) AF: 0.000501 AC: 1 AN: 1998

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.025815), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

De Lange syndrome Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.2

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: rs567891305; hg19: chr5-36877200; COSMIC: COSV99239964;