rs587783949

Positions:

• chr5-37010200-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP6_Moderate

The NM_133433.4(NIPBL):​c.4535A>T​(p.Asn1512Ile) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely benign (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: NIPBL NM_133433.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 6.06

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), NIPBL. . Gene score misZ 5.5737 (greater than the threshold 3.09). Trascript score misZ 6.6817 (greater than threshold 3.09). GenCC has associacion of gene with Cornelia de Lange syndrome, Cornelia de Lange syndrome 1.
• BP6: Variant 5-37010200-A-T is Benign according to our data. Variant chr5-37010200-A-T is described in ClinVar as [Likely_benign]. Clinvar id is 159117.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NIPBL	NM_133433.4	c.4535A>T	p.Asn1512Ile	missense_variant	21/47	ENST00000282516.13	NP_597677.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NIPBL	ENST00000282516.13	c.4535A>T	p.Asn1512Ile	missense_variant	21/47	1	NM_133433.4	ENSP00000282516	P1
NIPBL	ENST00000448238.2	c.4535A>T	p.Asn1512Ile	missense_variant	21/46	1		ENSP00000406266
NIPBL	ENST00000652901.1	c.4535A>T	p.Asn1512Ile	missense_variant	21/46			ENSP00000499536

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Feb 08, 2013

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Pathogenic	0.16	D
BayesDel_noAF	Uncertain	0.0
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.26	T;.
Eigen	Uncertain	0.23
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.86	D;D
M_CAP	Benign	0.047	D
MetaRNN	Uncertain	0.46	T;T
MetaSVM	Uncertain	0.41	D
MutationAssessor	Benign	0.34	N;N
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-1.9	N;N
REVEL	Uncertain	0.40
Sift	Benign	0.062	T;T
Sift4G	Benign	0.18	T;T
Polyphen		0.60	P;P
Vest4		0.61
MutPred		0.15		Gain of helix (P = 0.062);Gain of helix (P = 0.062);
MVP		0.83
MPC		1.3
ClinPred		0.40	T
GERP RS		5.9
Varity_R		0.18
gMVP		0.25

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

LitVar

Other links and lift over

dbSNP: rs587783949; hg19: chr5-37010302;