rs587784001

Variant names:

• chr5-37044630-T-C
• rs587784001
• NM_133433.4:c.6250-6T>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Moderate BP6_Moderate

The NM_133433.4(NIPBL):​c.6250-6T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,459,100 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: NIPBL NM_133433.4 splice_region, intron
• Scores: Splicing: ADA: 0.009884
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.11
• Publications: 0 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.38).
• BP6: Variant 5-37044630-T-C is Benign according to our data. Variant chr5-37044630-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 159182.Status of the report is criteria_provided_single_submitter, 1 stars.

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.6250-6T>C		splice_region intron	N/A	NP_597677.2
	NIPBL	NM_001438586.1		c.6250-6T>C		splice_region intron	N/A	NP_001425515.1
	NIPBL	NM_015384.5		c.6250-6T>C		splice_region 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.6250-6T>C		splice_region intron	N/A	ENSP00000282516.8
	NIPBL	ENST00000448238.2	TSL:1	c.6250-6T>C		splice_region intron	N/A	ENSP00000406266.2
	NIPBL	ENST00000652901.1		c.6250-6T>C		splice_region intron	N/A	ENSP00000499536.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1459100 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 726006

African (AFR) AF: 0.00 AC: 0 AN: 33424

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26104

East Asian (EAS) AF: 0.00 AC: 0 AN: 39642

South Asian (SAS) AF: 0.00 AC: 0 AN: 86130

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53384

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5700

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1109692

Other (OTH) AF: 0.00 AC: 0 AN: 60306

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.38
CADD	Benign	16
DANN	Benign	0.86
PhyloP100		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0099
dbscSNV1_RF	Benign	0.068
SpliceAI score (max)		0.24		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.24		Position offset: 6

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

Other links and lift over

dbSNP: rs587784001; hg19: chr5-37044732;