5-36877015-A-C

Variant summary

Our verdict is Benign. Variant got -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

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]

ACMG classification

Verdict is Benign. Variant got -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 male gnomad4 subpopulation. Median coverage is 30. This position pass quality control queck.
• BS2: High AC in GnomAd at 99 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NIPBL	NM_133433.4	c.-243A>C		5_prime_UTR_variant	1/47	ENST00000282516.13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NIPBL	ENST00000282516.13	c.-243A>C		5_prime_UTR_variant	1/47	1	NM_133433.4	P1
NIPBL	ENST00000448238.2	c.-243A>C		5_prime_UTR_variant	1/46	1
NIPBL	ENST00000652901.1	c.-243A>C		5_prime_UTR_variant	1/46

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

Gnomad4 AFR exome AF: 0.000332

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00127

Gnomad4 EAS exome AF: 0.000200

Gnomad4 SAS exome AF: 0.00222

Gnomad4 FIN exome AF: 0.000153

Gnomad4 NFE exome AF: 0.00103

Gnomad4 OTH exome AF: 0.000838

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

Gnomad4 AFR AF: 0.000266

Gnomad4 AMR AF: 0.000590

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.000197

Gnomad4 SAS AF: 0.00335

Gnomad4 FIN AF: 0.0000948

Gnomad4 NFE AF: 0.000855

Gnomad4 OTH AF: 0.000475

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

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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
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

Publications

LitVar

Other links and lift over

dbSNP: rs544681871; hg19: chr5-36877117;