NM_133433.4:c.3856-12A>G

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 2P and 8B. PM2BP4_StrongBS1

The NM_133433.4(NIPBL):​c.3856-12A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000375 in 1,332,544 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.000020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000017 ( 0 hom. )

Consequence

NIPBL
NM_133433.4 intron

Scores

2
Splicing: ADA: 0.00001255
2

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.612

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 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

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.7).
BS1
Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0000197 (3/152208) while in subpopulation AFR AF = 0.0000722 (3/41570). AF 95% confidence interval is 0.0000191. There are 0 homozygotes in GnomAd4. There are 0 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
NIPBLNM_133433.4 linkc.3856-12A>G intron_variant Intron 16 of 46 ENST00000282516.13 NP_597677.2 Q6KC79-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
NIPBLENST00000282516.13 linkc.3856-12A>G intron_variant Intron 16 of 46 1 NM_133433.4 ENSP00000282516.8 Q6KC79-1
NIPBLENST00000448238.2 linkc.3856-12A>G intron_variant Intron 16 of 45 1 ENSP00000406266.2 Q6KC79-2
NIPBLENST00000652901.1 linkc.3856-12A>G intron_variant Intron 16 of 45 ENSP00000499536.1 A0A590UJS4

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
152090
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000724
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.00000799
AC:
2
AN:
250426
AF XY:
0.00
show subpopulations
Gnomad AFR exome
AF:
0.000124
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000169
AC:
2
AN:
1180336
Hom.:
0
Cov.:
17
AF XY:
0.00
AC XY:
0
AN XY:
601574
show subpopulations
African (AFR)
AF:
0.0000713
AC:
2
AN:
28032
American (AMR)
AF:
0.00
AC:
0
AN:
44296
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
24380
East Asian (EAS)
AF:
0.00
AC:
0
AN:
38278
South Asian (SAS)
AF:
0.00
AC:
0
AN:
80496
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53180
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5262
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
855524
Other (OTH)
AF:
0.00
AC:
0
AN:
50888
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.475
Heterozygous variant carriers
0
1
1
2
2
3
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.0000197
AC:
3
AN:
152208
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74402
show subpopulations
African (AFR)
AF:
0.0000722
AC:
3
AN:
41570
American (AMR)
AF:
0.00
AC:
0
AN:
15298
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3464
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5188
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4824
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10616
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
294
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
67932
Other (OTH)
AF:
0.00
AC:
0
AN:
2110
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.608
Heterozygous variant carriers
0
1
1
2
2
3
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.00
Hom.:
0
Bravo
AF:
0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.70
CADD
Benign
10
DANN
Benign
0.82
PhyloP100
-0.61

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.000013
dbscSNV1_RF
Benign
0.018
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

Other links and lift over

dbSNP: rs199847583; hg19: chr5-37006447; API