NM_133433.4:c.-312T>A

Variant names:

• chr5-36876946-T-A
• rs540966156
• NM_133433.4:c.-312T>A

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_133433.4(NIPBL):​c.-312T>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00372 in 347,926 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0029 (4 hom., cov: 29)
  • Exomes 𝑓: 0.0043 (2 hom.)
• Consequence: NIPBL NM_133433.4 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.15

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

Verdict is Benign. Variant got -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.38).
• BP6: Variant 5-36876946-T-A is Benign according to our data. Variant chr5-36876946-T-A is described in ClinVar as [Likely_benign]. Clinvar id is 353366.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00288 (429/148726) while in subpopulation AMR AF= 0.00498 (75/15064). AF 95% confidence interval is 0.00407. There are 4 homozygotes in gnomad4. There are 198 alleles in male gnomad4 subpopulation. Median coverage is 29. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 429 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NIPBL	NM_133433.4	c.-312T>A		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	c.-312T>A		5_prime_UTR_variant	Exon 1 of 47	1	NM_133433.4	ENSP00000282516.8
NIPBL	ENST00000448238	c.-312T>A		5_prime_UTR_variant	Exon 1 of 46	1		ENSP00000406266.2
NIPBL	ENST00000652901	c.-312T>A		5_prime_UTR_variant	Exon 1 of 46			ENSP00000499536.1
NIPBL-DT	ENST00000649921.1	n.-246A>T		upstream_gene_variant

Frequencies

GnomAD3 genomes AF: 0.00287 AC: 427 AN: 148640 Hom.: 4 Cov.: 29

Gnomad AFR AF: 0.000820

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00499

Gnomad ASJ AF: 0.00989

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00304

Gnomad FIN AF: 0.0000995

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00392

Gnomad OTH AF: 0.00342

GnomAD4 exome AF: 0.00434 AC: 864 AN: 199200 Hom.: 2 Cov.: 0 AF XY: 0.00456 AC XY: 465 AN XY: 101862

Gnomad4 AFR exome AF: 0.00113

Gnomad4 AMR exome AF: 0.00252

Gnomad4 ASJ exome AF: 0.00953

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00539

Gnomad4 FIN exome AF: 0.000271

Gnomad4 NFE exome AF: 0.00533

Gnomad4 OTH exome AF: 0.00463

GnomAD4 genome AF: 0.00288 AC: 429 AN: 148726 Hom.: 4 Cov.: 29 AF XY: 0.00273 AC XY: 198 AN XY: 72526

Gnomad4 AFR AF: 0.000818

Gnomad4 AMR AF: 0.00498

Gnomad4 ASJ AF: 0.00989

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00348

Gnomad4 FIN AF: 0.0000995

Gnomad4 NFE AF: 0.00392

Gnomad4 OTH AF: 0.00339

Alfa AF: 0.00254 Hom.: 1

Bravo AF: 0.00258

Asia WGS AF: 0.00260 AC: 9 AN: 3476

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cornelia de Lange syndrome 1 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

not provided Benign:1

Feb 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NIPBL: BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.38
CADD	Benign	19
DANN	Benign	0.91

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs540966156; hg19: chr5-36877048;