5-37010104-T-C

Position:

• chr5-37010104-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_133433.4(NIPBL):​c.4439T>C​(p.Met1480Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,459,608 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: NIPBL NM_133433.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.901

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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.06917876).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NIPBL	NM_133433.4	c.4439T>C	p.Met1480Thr	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.4439T>C	p.Met1480Thr	missense_variant	21/47	1	NM_133433.4	ENSP00000282516.8
NIPBL	ENST00000448238.2	c.4439T>C	p.Met1480Thr	missense_variant	21/46	1		ENSP00000406266.2
NIPBL	ENST00000652901.1	c.4439T>C	p.Met1480Thr	missense_variant	21/46			ENSP00000499536.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1459608 Hom.: 0 Cov.: 29 AF XY: 0.00000138 AC XY: 1 AN XY: 726292

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.01e-7

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000329 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.048
BayesDel_addAF	Benign	-0.016	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	17
DANN	Benign	0.71
DEOGEN2	Benign	0.093	T;.
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.13
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.77	T;T
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.069	T;T
MetaSVM	Benign	-0.71	T
MutationAssessor	Benign	0.0	N;N
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	0.68	N;N
REVEL	Benign	0.19
Sift	Benign	0.62	T;T
Sift4G	Benign	0.60	T;T
Polyphen		0.0	B;B
Vest4		0.20
MVP		0.45
MPC		1.0
ClinPred		0.22	T
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.056
gMVP		0.14

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: rs587783948; hg19: chr5-37010206;