rs587783916

Variant names:

• chr5-36986289-A-G
• rs587783916
• NM_133433.4:c.3109A>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 1P and 5B. PP3 BS1_Supporting BS2

The NM_133433.4(NIPBL):​c.3109A>G​(p.Lys1037Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000442 in 1,356,362 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000044 (0 hom.)
• Consequence: NIPBL NM_133433.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:6
• Conservation: PhyloP100: 8.16
• Publications: 1 publications found

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

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.785
• BS1: Variant frequency is greater than expected in population amr. GnomAdExome4 allele frequency = 0.00000442 (6/1356362) while in subpopulation AMR AF = 0.0000696 (2/28716). AF 95% confidence interval is 0.0000197. There are 0 homozygotes in GnomAdExome4. There are 4 alleles in the male GnomAdExome4 subpopulation. Median coverage is 28. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAdExome4 at 6 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NIPBL	NM_133433.4	MANE Select	c.3109A>G	p.Lys1037Glu	missense	Exon 10 of 47	NP_597677.2
	NIPBL	NM_001438586.1		c.3109A>G	p.Lys1037Glu	missense	Exon 10 of 47	NP_001425515.1
	NIPBL	NM_015384.5		c.3109A>G	p.Lys1037Glu	missense	Exon 10 of 46	NP_056199.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NIPBL	ENST00000282516.13	TSL:1 MANE Select	c.3109A>G	p.Lys1037Glu	missense	Exon 10 of 47	ENSP00000282516.8	Q6KC79-1
	NIPBL	ENST00000448238.2	TSL:1	c.3109A>G	p.Lys1037Glu	missense	Exon 10 of 46	ENSP00000406266.2	Q6KC79-2
	NIPBL	ENST00000652901.1		c.3109A>G	p.Lys1037Glu	missense	Exon 10 of 46	ENSP00000499536.1	A0A590UJS4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000590 AC: 1 AN: 169396 AF XY: 0.0000110

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000495

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: 0.00000442 AC: 6 AN: 1356362 Hom.: 0 Cov.: 28 AF XY: 0.00000600 AC XY: 4 AN XY: 667090

African (AFR) AF: 0.00 AC: 0 AN: 30120

American (AMR) AF: 0.0000696 AC: 2 AN: 28716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20306

East Asian (EAS) AF: 0.00 AC: 0 AN: 38980

South Asian (SAS) AF: 0.0000587 AC: 4 AN: 68182

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 42348

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5152

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1066320

Other (OTH) AF: 0.00 AC: 0 AN: 56238

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	4	-	Cornelia de Lange syndrome 1 (4)
-	1	-	Inborn genetic diseases (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.77
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.22
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.20	T
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.88	D
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.78	D
MetaSVM	Uncertain	0.67	D
MutationAssessor	Benign	1.4	L
PhyloP100		8.2
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-0.47	N
REVEL	Uncertain	0.51
Sift	Uncertain	0.0040	D
Sift4G	Benign	0.41	T
Polyphen		0.99	D
Vest4		0.68
MutPred		0.36		Loss of MoRF binding (P = 0.0011)
MVP		0.87
MPC		0.52
ClinPred		0.65	D
GERP RS		6.1
Varity_R		0.28
gMVP		0.61
Mutation Taster		=83/17	polymorphism

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

Other links and lift over

dbSNP: rs587783916; hg19: chr5-36986391;