5-37052471-G-T

Variant names:

• chr5-37052471-G-T
• NM_133433.4:c.7168G>T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PM5 PP2

The NM_133433.4(NIPBL):​c.7168G>T​(p.Ala2390Ser) 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A2390T) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NIPBL NM_133433.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.45

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 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr5-37052471-G-A is described in Lovd as [Pathogenic].
• 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NIPBL	NM_133433.4	c.7168G>T	p.Ala2390Ser	missense_variant	Exon 42 of 47	ENST00000282516.13	NP_597677.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NIPBL	ENST00000282516.13	c.7168G>T	p.Ala2390Ser	missense_variant	Exon 42 of 47	1	NM_133433.4	ENSP00000282516.8
NIPBL	ENST00000448238.2	c.7168G>T	p.Ala2390Ser	missense_variant	Exon 42 of 46	1		ENSP00000406266.2
NIPBL	ENST00000652901.1	c.7168G>T	p.Ala2390Ser	missense_variant	Exon 42 of 46			ENSP00000499536.1
NIPBL	ENST00000514335.1	n.1050G>T		non_coding_transcript_exon_variant	Exon 2 of 7	2

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 provided Uncertain:1

Feb 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NIPBL: PM2, PM5 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Uncertain	0.065	T
BayesDel_noAF	Benign	-0.14
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.63	D;.
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D;D
M_CAP	Benign	0.051	D
MetaRNN	Uncertain	0.57	D;D
MetaSVM	Benign	-0.38	T
MutationAssessor	Benign	2.0	M;M
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-1.3	N;N
REVEL	Benign	0.25
Sift	Benign	0.056	T;T
Sift4G	Benign	0.22	T;T
Polyphen		0.95	P;P
Vest4		0.55
MutPred		0.60		Gain of disorder (P = 0.017);Gain of disorder (P = 0.017);
MVP		0.77
MPC		1.5
ClinPred		0.97	D
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.63
gMVP		0.60

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-37052573; COSMIC: COSV56960981;