5-36876946-T-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_ModerateBS1BS2

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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0029 ( 4 hom., cov: 29)

Exomes 𝑓: 0.0043 ( 2 hom. )

Consequence

NIPBL
NM_133433.4 5_prime_UTR

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 2.15

Publications

0 publications found

Variant links:

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 links:

NIPBL-DT (HGNC:51293): (NIPBL divergent transcript)

NIPBL-DT links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.38).

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 the male GnomAd4 subpopulation. Median coverage is 29. This position passed quality control check.

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 link	c.-312T>A		5_prime_UTR_variant	Exon 1 of 47	ENST00000282516.13	NP_597677.2	Q6KC79-1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
NIPBL	ENST00000282516.13 link	c.-312T>A	5_prime_UTR_variant	Exon 1 of 47	1	NM_133433.4	ENSP00000282516.8	Q6KC79-1
NIPBL	ENST00000448238.2 link	c.-312T>A	5_prime_UTR_variant	Exon 1 of 46	1		ENSP00000406266.2	Q6KC79-2
NIPBL	ENST00000652901.1 link	c.-312T>A	5_prime_UTR_variant	Exon 1 of 46			ENSP00000499536.1	A0A590UJS4
NIPBL-DT	ENST00000649921.1 link	n.-246A>T	upstream_gene_variant

Frequencies

GnomAD3 genomes

AF:

0.00287

AC:

427

AN:

148640

Hom.:

Cov.:

show subpopulations

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.:

Cov.:

AF XY:

0.00456

AC XY:

465

AN XY:

101862

show subpopulations

African (AFR)

AF:

0.00113

AC:

AN:

5324

American (AMR)

AF:

0.00252

AC:

AN:

5958

Ashkenazi Jewish (ASJ)

AF:

0.00953

AC:

AN:

7136

East Asian (EAS)

AF:

0.00

AC:

AN:

18544

South Asian (SAS)

AF:

0.00539

AC:

AN:

2598

European-Finnish (FIN)

AF:

0.000271

AC:

AN:

18452

Middle Eastern (MID)

AF:

0.0175

AC:

AN:

1028

European-Non Finnish (NFE)

AF:

0.00533

AC:

678

AN:

127214

Other (OTH)

AF:

0.00463

AC:

AN:

12946

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

114

152

190

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00288

AC:

429

AN:

148726

Hom.:

Cov.:

AF XY:

0.00273

AC XY:

198

AN XY:

72526

show subpopulations

African (AFR)

AF:

0.000818

AC:

AN:

40344

American (AMR)

AF:

0.00498

AC:

AN:

15064

Ashkenazi Jewish (ASJ)

AF:

0.00989

AC:

AN:

3438

East Asian (EAS)

AF:

0.00

AC:

AN:

4850

South Asian (SAS)

AF:

0.00348

AC:

AN:

4594

European-Finnish (FIN)

AF:

0.0000995

AC:

AN:

10046

Middle Eastern (MID)

AF:

0.00

AC:

AN:

276

European-Non Finnish (NFE)

AF:

0.00392

AC:

263

AN:

67148

Other (OTH)

AF:

0.00339

AC:

AN:

2066

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

101

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00254

Hom.:

Bravo

AF:

0.00258

Asia WGS

AF:

0.00260

AC:

AN:

3476

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

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

(source)

DANN

Benign

0.91

PhyloP100

2.1

PromoterAI

0.34

Neutral

(source)

Mutation Taster

=298/2

polymorphism

(source)

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

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5-36876946-T-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over