5-36876834-TC-TCC

Variant names:

• chr5-36876834-T-TC
• rs886060553
• NM_133433.4:c.-416dupC

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6 BA1

The NM_133433.4(NIPBL):​c.-416dupC variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0145 in 80,170 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0053 (0 hom., cov: 25)
  • Exomes 𝑓: 0.046 (2 hom.)
• Consequence: NIPBL NM_133433.4 5_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 1.57
• 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-DT (HGNC:51293): (NIPBL divergent transcript)

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP6: Variant 5-36876834-T-TC is Benign according to our data. Variant chr5-36876834-T-TC is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 353362.
• BA1: GnomAdExome4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0554 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_133433.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NIPBL	NM_133433.4	MANE Select	c.-416dupC		5_prime_UTR	Exon 1 of 47	NP_597677.2
	NIPBL	NM_001438586.1		c.-416dupC		5_prime_UTR	Exon 1 of 47	NP_001425515.1
	NIPBL	NM_015384.5		c.-416dupC		5_prime_UTR	Exon 1 of 46	NP_056199.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NIPBL	ENST00000282516.13	TSL:1 MANE Select	c.-416dupC		5_prime_UTR	Exon 1 of 47	ENSP00000282516.8	Q6KC79-1
	NIPBL	ENST00000448238.2	TSL:1	c.-416dupC		5_prime_UTR	Exon 1 of 46	ENSP00000406266.2	Q6KC79-2
	NIPBL	ENST00000652901.1		c.-416dupC		5_prime_UTR	Exon 1 of 46	ENSP00000499536.1	A0A590UJS4

Frequencies

GnomAD3 genomes AF: 0.00533 AC: 330 AN: 61944 Hom.: 0 Cov.: 25

Gnomad AFR AF: 0.00230

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00405

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000732

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00181

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00852

Gnomad OTH AF: 0.00426

GnomAD4 exome AF: 0.0459 AC: 834 AN: 18172 Hom.: 2 Cov.: 0 AF XY: 0.0451 AC XY: 426 AN XY: 9436

African (AFR) AF: 0.0124 AC: 5 AN: 402

American (AMR) AF: 0.0139 AC: 7 AN: 502

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 478

East Asian (EAS) AF: 0.00326 AC: 6 AN: 1838

South Asian (SAS) AF: 0.00296 AC: 1 AN: 338

European-Finnish (FIN) AF: 0.0353 AC: 60 AN: 1702

Middle Eastern (MID) AF: 0.0238 AC: 2 AN: 84

European-Non Finnish (NFE) AF: 0.0591 AC: 690 AN: 11682

Other (OTH) AF: 0.0550 AC: 63 AN: 1146

GnomAD4 genome AF: 0.00532 AC: 330 AN: 61998 Hom.: 0 Cov.: 25 AF XY: 0.00504 AC XY: 149 AN XY: 29542

African (AFR) AF: 0.00230 AC: 38 AN: 16536

American (AMR) AF: 0.00405 AC: 26 AN: 6426

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 1512

East Asian (EAS) AF: 0.000731 AC: 1 AN: 1368

South Asian (SAS) AF: 0.00145 AC: 2 AN: 1380

European-Finnish (FIN) AF: 0.00181 AC: 7 AN: 3860

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 116

European-Non Finnish (NFE) AF: 0.00852 AC: 252 AN: 29564

Other (OTH) AF: 0.00424 AC: 4 AN: 944

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	De Lange syndrome (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.6
Mutation Taster		=298/2	polymorphism

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: rs886060553; hg19: chr5-36876936;