chr5-36876834-TC-T

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1 BS2

The NM_133433.4(NIPBL):​c.-416delC variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00358 in 79,382 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00098 (0 hom., cov: 25)
  • Exomes 𝑓: 0.013 (0 hom.)
• Consequence: NIPBL NM_133433.4 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• 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 -8 ACMG points.

• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000984 (61/61990) while in subpopulation AFR AF = 0.0023 (38/16536). AF 95% confidence interval is 0.00172. There are 0 homozygotes in GnomAd4. There are 36 alleles in the male GnomAd4 subpopulation. Median coverage is 25. This position passed quality control check.
• BS2: High AC in GnomAd4 at 61 AD gene.

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.-416delC		5_prime_UTR	Exon 1 of 47	NP_597677.2
	NIPBL	NM_001438586.1		c.-416delC		5_prime_UTR	Exon 1 of 47	NP_001425515.1
	NIPBL	NM_015384.5		c.-416delC		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.-416delC		5_prime_UTR	Exon 1 of 47	ENSP00000282516.8	Q6KC79-1
	NIPBL	ENST00000448238.2	TSL:1	c.-416delC		5_prime_UTR	Exon 1 of 46	ENSP00000406266.2	Q6KC79-2
	NIPBL	ENST00000652901.1		c.-416delC		5_prime_UTR	Exon 1 of 46	ENSP00000499536.1	A0A590UJS4

Frequencies

GnomAD3 genomes AF: 0.000985 AC: 61 AN: 61936 Hom.: 0 Cov.: 25

Gnomad AFR AF: 0.00230

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000156

Gnomad ASJ AF: 0.00132

Gnomad EAS AF: 0.00146

Gnomad SAS AF: 0.000726

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000575

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0128 AC: 223 AN: 17392 Hom.: 0 Cov.: 0 AF XY: 0.0129 AC XY: 116 AN XY: 9008

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

African (AFR) AF: 0.0376 AC: 14 AN: 372

American (AMR) AF: 0.0212 AC: 10 AN: 472

Ashkenazi Jewish (ASJ) AF: 0.0313 AC: 14 AN: 448

East Asian (EAS) AF: 0.0142 AC: 25 AN: 1764

South Asian (SAS) AF: 0.00299 AC: 1 AN: 334

European-Finnish (FIN) AF: 0.00306 AC: 5 AN: 1632

Middle Eastern (MID) AF: 0.0256 AC: 2 AN: 78

European-Non Finnish (NFE) AF: 0.0121 AC: 136 AN: 11202

Other (OTH) AF: 0.0147 AC: 16 AN: 1090

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.000984 AC: 61 AN: 61990 Hom.: 0 Cov.: 25 AF XY: 0.00122 AC XY: 36 AN XY: 29532

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

American (AMR) AF: 0.000156 AC: 1 AN: 6420

Ashkenazi Jewish (ASJ) AF: 0.00132 AC: 2 AN: 1512

East Asian (EAS) AF: 0.00146 AC: 2 AN: 1372

South Asian (SAS) AF: 0.000725 AC: 1 AN: 1380

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 3860

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

European-Non Finnish (NFE) AF: 0.000575 AC: 17 AN: 29558

Other (OTH) AF: 0.00 AC: 0 AN: 944

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.6
Mutation Taster		=281/19	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;