dbSNP rs190086412: NIPBL:p.Asn1897Ser (chr5-37024700-A-G) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4BP6BS1BS2

The NM_133433.4(NIPBL):c.5690A>G(p.Asn1897Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000546 in 1,612,480 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000092 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000051 ( 0 hom. )

Consequence

NIPBL
NM_133433.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:4

Conservation

PhyloP100: 8.90

Publications

1 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

NIPBL links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (MetaRNN=0.33223525).

BP6

Variant 5-37024700-A-G is Benign according to our data. Variant chr5-37024700-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 159155.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0000919 (14/152372) while in subpopulation SAS AF = 0.000207 (1/4828). AF 95% confidence interval is 0.0000626. There are 0 homozygotes in GnomAd4. There are 5 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 14 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_133433.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
NIPBL	NM_133433.4	MANE Select	c.5690A>G	p.Asn1897Ser	missense	Exon 30 of 47	NP_597677.2
NIPBL	NM_001438586.1		c.5690A>G	p.Asn1897Ser	missense	Exon 30 of 47	NP_001425515.1
NIPBL	NM_015384.5		c.5690A>G	p.Asn1897Ser	missense	Exon 30 of 46	NP_056199.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NIPBL	ENST00000282516.13	TSL:1 MANE Select	c.5690A>G	p.Asn1897Ser	missense	Exon 30 of 47	ENSP00000282516.8	Q6KC79-1
NIPBL	ENST00000448238.2	TSL:1	c.5690A>G	p.Asn1897Ser	missense	Exon 30 of 46	ENSP00000406266.2	Q6KC79-2
NIPBL	ENST00000652901.1		c.5690A>G	p.Asn1897Ser	missense	Exon 30 of 46	ENSP00000499536.1	A0A590UJS4

Frequencies

GnomAD3 genomes

AF:

0.0000920

AC:

AN:

152254

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.0000718

AC:

AN:

250664

AF XY:

0.0000738

show subpopulations

Gnomad AFR exome

AF:

0.0000617

Gnomad AMR exome

AF:

0.0000580

Gnomad ASJ exome

AF:

0.0000993

Gnomad EAS exome

AF:

0.000163

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000618

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000507

AC:

AN:

1460108

Hom.:

Cov.:

AF XY:

0.0000564

AC XY:

AN XY:

726326

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33452

American (AMR)

AF:

0.0000671

AC:

AN:

44690

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26092

East Asian (EAS)

AF:

0.000278

AC:

AN:

39518

South Asian (SAS)

AF:

0.0000581

AC:

AN:

86064

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53330

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5742

European-Non Finnish (NFE)

AF:

0.0000432

AC:

AN:

1110918

Other (OTH)

AF:

0.0000829

AC:

AN:

60302

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.0000919

AC:

AN:

152372

Hom.:

Cov.:

AF XY:

0.0000671

AC XY:

AN XY:

74518

show subpopulations

African (AFR)

AF:

0.000144

AC:

AN:

41594

American (AMR)

AF:

0.000196

AC:

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.000207

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

68032

Other (OTH)

AF:

0.000473

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.514

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.0000258

Hom.:

Bravo

AF:

0.000113

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ExAC

AF:

0.0000741

AC:

Asia WGS

AF:

0.000578

AC:

AN:

3476

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Cornelia de Lange syndrome 1 (2)

Inborn genetic diseases (1)

not provided (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.28

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.70

Eigen

Uncertain

0.55

Eigen_PC

Uncertain

0.61

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.94

M_CAP

Uncertain

0.18

MetaRNN

Benign

0.33

MetaSVM

Uncertain

-0.071

MutationAssessor

Benign

1.7

PhyloP100

8.9

PrimateAI

Pathogenic

0.89

PROVEAN

Uncertain

-4.1

REVEL

Uncertain

0.47

Sift

Benign

0.12

Sift4G

Pathogenic

0.0

Polyphen

0.78

Vest4

0.66

MVP

0.81

MPC

1.8

ClinPred

0.13

GERP RS

5.6

Varity_R

0.38

gMVP

0.37

Mutation Taster

=60/40

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over