NM_133433.4:c.-243A>C

Variant names:

• chr5-36877015-A-C
• rs544681871
• NM_133433.4:c.-243A>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_133433.4(NIPBL):​c.-243A>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000758 in 369,454 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.00065 (0 hom., cov: 30)
  • Exomes 𝑓: 0.00083 (1 hom.)
• Consequence: NIPBL NM_133433.4 5_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.457
• 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.59).
• BP6: Variant 5-36877015-A-C is Benign according to our data. Variant chr5-36877015-A-C is described in ClinVar as [Benign]. Clinvar id is 353369.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000653 (99/151592) while in subpopulation SAS AF = 0.00335 (16/4780). AF 95% confidence interval is 0.0021. There are 0 homozygotes in GnomAd4. There are 52 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.
• BS2: High AC in GnomAd4 at 99 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NIPBL	NM_133433.4	c.-243A>C		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.-243A>C		5_prime_UTR_variant	Exon 1 of 47	1	NM_133433.4	ENSP00000282516.8
NIPBL	ENST00000448238.2	c.-243A>C		5_prime_UTR_variant	Exon 1 of 46	1		ENSP00000406266.2
NIPBL	ENST00000652901.1	c.-243A>C		5_prime_UTR_variant	Exon 1 of 46			ENSP00000499536.1

Frequencies

GnomAD3 genomes AF: 0.000654 AC: 99 AN: 151476 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.000267

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000591

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.000196

Gnomad SAS AF: 0.00334

Gnomad FIN AF: 0.0000948

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000855

Gnomad OTH AF: 0.000480

GnomAD4 exome AF: 0.000831 AC: 181 AN: 217862 Hom.: 1 Cov.: 0 AF XY: 0.000809 AC XY: 90 AN XY: 111186

African (AFR) AF: 0.000332 AC: 2 AN: 6024

American (AMR) AF: 0.00 AC: 0 AN: 6488

Ashkenazi Jewish (ASJ) AF: 0.00127 AC: 10 AN: 7904

East Asian (EAS) AF: 0.000200 AC: 4 AN: 19956

South Asian (SAS) AF: 0.00222 AC: 6 AN: 2700

European-Finnish (FIN) AF: 0.000153 AC: 3 AN: 19652

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1180

European-Non Finnish (NFE) AF: 0.00103 AC: 144 AN: 139636

Other (OTH) AF: 0.000838 AC: 12 AN: 14322

GnomAD4 genome AF: 0.000653 AC: 99 AN: 151592 Hom.: 0 Cov.: 30 AF XY: 0.000702 AC XY: 52 AN XY: 74070

African (AFR) AF: 0.000266 AC: 11 AN: 41334

American (AMR) AF: 0.000590 AC: 9 AN: 15244

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3472

East Asian (EAS) AF: 0.000197 AC: 1 AN: 5088

South Asian (SAS) AF: 0.00335 AC: 16 AN: 4780

European-Finnish (FIN) AF: 0.0000948 AC: 1 AN: 10548

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000855 AC: 58 AN: 67820

Other (OTH) AF: 0.000475 AC: 1 AN: 2104

Alfa AF: 0.000971 Hom.: 0

Bravo AF: 0.000578

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Cornelia de Lange syndrome 1 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	14
DANN	Benign	0.90
PhyloP100		0.46
PromoterAI		0.057	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		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: rs544681871; hg19: chr5-36877117;