chr5-36986312-T-G

Variant names:

• chr5-36986312-T-G
• rs457583
• NM_133433.4:c.3121+11T>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_133433.4(NIPBL):​c.3121+11T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00163 in 1,454,432 control chromosomes in the GnomAD database, including 35 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0086 (24 hom., cov: 32)
  • Exomes 𝑓: 0.00081 (11 hom.)
• Consequence: NIPBL NM_133433.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.497
• 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 5-36986312-T-G is Benign according to our data. Variant chr5-36986312-T-G is described in ClinVar as Benign. ClinVar VariationId is 159074.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00865 (1317/152284) while in subpopulation AFR AF = 0.0298 (1239/41564). AF 95% confidence interval is 0.0284. There are 24 homozygotes in GnomAd4. There are 613 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1317 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.3121+11T>G		intron	N/A	NP_597677.2
	NIPBL	NM_001438586.1		c.3121+11T>G		intron	N/A	NP_001425515.1
	NIPBL	NM_015384.5		c.3121+11T>G		intron	N/A	NP_056199.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NIPBL	ENST00000282516.13	TSL:1 MANE Select	c.3121+11T>G		intron	N/A	ENSP00000282516.8	Q6KC79-1
	NIPBL	ENST00000448238.2	TSL:1	c.3121+11T>G		intron	N/A	ENSP00000406266.2	Q6KC79-2
	NIPBL	ENST00000652901.1		c.3121+11T>G		intron	N/A	ENSP00000499536.1	A0A590UJS4

Frequencies

GnomAD3 genomes AF: 0.00866 AC: 1317 AN: 152166 Hom.: 24 Cov.: 32

Gnomad AFR AF: 0.0299

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00373

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00670

GnomAD2 exomes AF: 0.00327 AC: 526 AN: 160884 AF XY: 0.00255

Gnomad AFR exome AF: 0.0344

Gnomad AMR exome AF: 0.00216

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000121

Gnomad OTH exome AF: 0.000267

GnomAD4 exome AF: 0.000809 AC: 1053 AN: 1302148 Hom.: 11 Cov.: 22 AF XY: 0.000723 AC XY: 463 AN XY: 640002

African (AFR) AF: 0.0294 AC: 856 AN: 29116

American (AMR) AF: 0.00230 AC: 62 AN: 26940

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19604

East Asian (EAS) AF: 0.00 AC: 0 AN: 38428

South Asian (SAS) AF: 0.0000634 AC: 4 AN: 63084

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39390

Middle Eastern (MID) AF: 0.00108 AC: 5 AN: 4646

European-Non Finnish (NFE) AF: 0.0000146 AC: 15 AN: 1026682

Other (OTH) AF: 0.00205 AC: 111 AN: 54258

GnomAD4 genome AF: 0.00865 AC: 1317 AN: 152284 Hom.: 24 Cov.: 32 AF XY: 0.00823 AC XY: 613 AN XY: 74464

African (AFR) AF: 0.0298 AC: 1239 AN: 41564

American (AMR) AF: 0.00373 AC: 57 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68020

Other (OTH) AF: 0.00663 AC: 14 AN: 2112

Alfa AF: 0.00905 Hom.: 4

Bravo AF: 0.0101

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Cornelia de Lange syndrome 1 (3)
-	-	3	not specified (3)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	13
DANN	Benign	0.72
PhyloP100		0.50
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs457583; hg19: chr5-36986414;