NM_133433.4:c.6145A>G

Variant names:

• chr5-37044383-A-G
• rs587783996
• NM_133433.4:c.6145A>G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP2 PP3

The NM_133433.4(NIPBL):​c.6145A>G​(p.Lys2049Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: NIPBL NM_133433.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.95

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the NIPBL gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 86 curated pathogenic missense variants (we use a threshold of 10). The gene has 69 curated benign missense variants. Gene score misZ: 5.5737 (above the threshold of 3.09). Trascript score misZ: 6.6817 (above the threshold of 3.09). GenCC associations: The gene is linked to Cornelia de Lange syndrome, Cornelia de Lange syndrome 1.
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NIPBL	NM_133433.4	c.6145A>G	p.Lys2049Glu	missense_variant	Exon 35 of 47	ENST00000282516.13	NP_597677.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NIPBL	ENST00000282516.13	c.6145A>G	p.Lys2049Glu	missense_variant	Exon 35 of 47	1	NM_133433.4	ENSP00000282516.8
NIPBL	ENST00000448238.2	c.6145A>G	p.Lys2049Glu	missense_variant	Exon 35 of 46	1		ENSP00000406266.2
NIPBL	ENST00000652901.1	c.6145A>G	p.Lys2049Glu	missense_variant	Exon 35 of 46			ENSP00000499536.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 17, 2019

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Benign	0.21	T;.
Eigen	Benign	0.12
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Benign	0.058	D
MetaRNN	Uncertain	0.68	D;D
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	1.5	L;L
PrimateAI	Pathogenic	0.92	D
PROVEAN	Benign	-1.3	N;N
REVEL	Benign	0.28
Sift	Benign	0.29	T;T
Sift4G	Benign	0.13	T;T
Polyphen		0.23	B;B
Vest4		0.79
MutPred		0.55		Loss of ubiquitination at K2049 (P = 0.0116);Loss of ubiquitination at K2049 (P = 0.0116);
MVP		0.89
MPC		2.3
ClinPred		0.68	D
GERP RS		5.6
Varity_R		0.43
gMVP		0.84

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.74		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.74		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs587783996; hg19: chr5-37044485;