5-37051759-ATTTTT-ATTTTTT

Variant names:

• chr5-37051759-A-AT
• rs757731487
• NM_133433.4:c.6955-9dupT

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6 BS1 BS2

The NM_133433.4(NIPBL):​c.6955-9dupT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00889 in 1,207,606 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 32)
  • Exomes 𝑓: 0.010 (0 hom.)
• Consequence: NIPBL NM_133433.4 splice_region, intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -0.231
• 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: Benign. The variant received -9 ACMG points.

• BP6: Variant 5-37051759-A-AT is Benign according to our data. Variant chr5-37051759-A-AT is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1950511.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000181 (27/149054) while in subpopulation EAS AF = 0.000588 (3/5102). AF 95% confidence interval is 0.000159. There are 0 homozygotes in GnomAd4. There are 14 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 27 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.6955-9dupT		splice_region intron	N/A	NP_597677.2
	NIPBL	NM_001438586.1		c.6955-9dupT		splice_region intron	N/A	NP_001425515.1
	NIPBL	NM_015384.5		c.6955-9dupT		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.6955-9dupT		splice_region intron	N/A	ENSP00000282516.8	Q6KC79-1
	NIPBL	ENST00000448238.2	TSL:1	c.6955-9dupT		splice_region intron	N/A	ENSP00000406266.2	Q6KC79-2
	NIPBL	ENST00000652901.1		c.6955-9dupT		splice_region intron	N/A	ENSP00000499536.1	A0A590UJS4

Frequencies

GnomAD3 genomes AF: 0.000181 AC: 27 AN: 148962 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000735

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000135

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000586

Gnomad SAS AF: 0.000212

Gnomad FIN AF: 0.000204

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000239

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00419 AC: 525 AN: 125324 AF XY: 0.00407

Gnomad AFR exome AF: 0.00159

Gnomad AMR exome AF: 0.00782

Gnomad ASJ exome AF: 0.00477

Gnomad EAS exome AF: 0.00526

Gnomad FIN exome AF: 0.000821

Gnomad NFE exome AF: 0.00363

Gnomad OTH exome AF: 0.00275

GnomAD4 exome AF: 0.0101 AC: 10704 AN: 1058552 Hom.: 0 Cov.: 18 AF XY: 0.00948 AC XY: 5023 AN XY: 529704

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00849 AC: 205 AN: 24142

American (AMR) AF: 0.00457 AC: 154 AN: 33704

Ashkenazi Jewish (ASJ) AF: 0.00493 AC: 92 AN: 18648

East Asian (EAS) AF: 0.00387 AC: 111 AN: 28708

South Asian (SAS) AF: 0.00570 AC: 365 AN: 64040

European-Finnish (FIN) AF: 0.00106 AC: 45 AN: 42560

Middle Eastern (MID) AF: 0.00589 AC: 27 AN: 4586

European-Non Finnish (NFE) AF: 0.0117 AC: 9335 AN: 798608

Other (OTH) AF: 0.00849 AC: 370 AN: 43556

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.000181 AC: 27 AN: 149054 Hom.: 0 Cov.: 32 AF XY: 0.000193 AC XY: 14 AN XY: 72658

African (AFR) AF: 0.0000733 AC: 3 AN: 40938

American (AMR) AF: 0.000134 AC: 2 AN: 14876

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3430

East Asian (EAS) AF: 0.000588 AC: 3 AN: 5102

South Asian (SAS) AF: 0.000213 AC: 1 AN: 4700

European-Finnish (FIN) AF: 0.000204 AC: 2 AN: 9798

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 288

European-Non Finnish (NFE) AF: 0.000239 AC: 16 AN: 66952

Other (OTH) AF: 0.00 AC: 0 AN: 2062

Alfa AF: 0.0124 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	Cornelia de Lange syndrome 1 (1)
-	1	-	Orofacial cleft 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.23
La Branchor		0.34
BranchPoint Hunter		4.0
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs757731487; hg19: chr5-37051861;