rs567891305

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr5-36877098-AC-A
• chr5-36877098-AC-ACC

Variant summary

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

The NM_133433.4(NIPBL):​c.-153delC variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000125 in 319,024 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 0.000049 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00019 (0 hom.)
• Consequence: NIPBL NM_133433.4 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• 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: Benign. The variant received -8 ACMG points.

• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0000487 (7/143824) while in subpopulation SAS AF = 0.000233 (1/4294). AF 95% confidence interval is 0.0000205. There are 0 homozygotes in GnomAd4. There are 4 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NIPBL	NM_133433.4	c.-153delC		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.-153delC		5_prime_UTR_variant	Exon 1 of 47	1	NM_133433.4	ENSP00000282516.8
NIPBL	ENST00000448238.2	c.-153delC		5_prime_UTR_variant	Exon 1 of 46	1		ENSP00000406266.2
NIPBL	ENST00000652901.1	c.-153delC		5_prime_UTR_variant	Exon 1 of 46			ENSP00000499536.1

Frequencies

GnomAD3 genomes AF: 0.0000487 AC: 7 AN: 143714 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: 0.00

Gnomad SAS AF: 0.000232

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000459

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000188 AC: 33 AN: 175200 Hom.: 0 Cov.: 0 AF XY: 0.000156 AC XY: 14 AN XY: 89962

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

African (AFR) AF: 0.000203 AC: 1 AN: 4934

American (AMR) AF: 0.00 AC: 0 AN: 5238

Ashkenazi Jewish (ASJ) AF: 0.000155 AC: 1 AN: 6436

East Asian (EAS) AF: 0.0000665 AC: 1 AN: 15036

South Asian (SAS) AF: 0.00 AC: 0 AN: 1602

European-Finnish (FIN) AF: 0.000124 AC: 2 AN: 16150

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 886

European-Non Finnish (NFE) AF: 0.000247 AC: 28 AN: 113432

Other (OTH) AF: 0.00 AC: 0 AN: 11486

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000487 AC: 7 AN: 143824 Hom.: 0 Cov.: 31 AF XY: 0.0000571 AC XY: 4 AN XY: 70090

African (AFR) AF: 0.0000772 AC: 3 AN: 38848

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

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 4678

South Asian (SAS) AF: 0.000233 AC: 1 AN: 4294

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9524

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

European-Non Finnish (NFE) AF: 0.0000459 AC: 3 AN: 65310

Other (OTH) AF: 0.00 AC: 0 AN: 1998

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.2
Mutation Taster		=267/33	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: rs567891305; hg19: chr5-36877200;