5-37064967-CAAA-CAA

Variant names:

• chr5-37064967-CA-C
• rs587783876
• NM_133433.4:c.*84delA

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP6_Moderate

The NM_133433.4(NIPBL):​c.*84delA variant causes a 3 prime UTR change. The variant allele was found at a frequency of 0.000337 in 1,526,394 control chromosomes in the GnomAD database, with no homozygous occurrence. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00037 (0 hom.)
• Consequence: NIPBL NM_133433.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 5.35
• 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: Likely_benign. The variant received -2 ACMG points.

• BP6: Variant 5-37064967-CA-C is Benign according to our data. Variant chr5-37064967-CA-C is described in CliVar as Benign. Clinvar id is 159023.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NIPBL	NM_133433.4	c.*84delA		3_prime_UTR_variant	Exon 47 of 47	ENST00000282516.13	NP_597677.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NIPBL	ENST00000282516.13	c.*84delA		3_prime_UTR_variant	Exon 47 of 47	1	NM_133433.4	ENSP00000282516.8
NIPBL	ENST00000514335.1	n.2422delA		non_coding_transcript_exon_variant	Exon 7 of 7	2
NIPBL	ENST00000652901.1	c.*443delA		3_prime_UTR_variant	Exon 46 of 46			ENSP00000499536.1

Frequencies

GnomAD3 genomes AF: 0.0000201 AC: 3 AN: 149282 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000493

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000195

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000372 AC: 512 AN: 1377000 Hom.: 0 Cov.: 23 AF XY: 0.000387 AC XY: 266 AN XY: 687394

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

African (AFR) AF: 0.000397 AC: 12 AN: 30248

American (AMR) AF: 0.000396 AC: 15 AN: 37918

Ashkenazi Jewish (ASJ) AF: 0.000366 AC: 9 AN: 24600

East Asian (EAS) AF: 0.0000515 AC: 2 AN: 38800

South Asian (SAS) AF: 0.000312 AC: 25 AN: 80068

European-Finnish (FIN) AF: 0.000495 AC: 24 AN: 48438

Middle Eastern (MID) AF: 0.000733 AC: 4 AN: 5458

European-Non Finnish (NFE) AF: 0.000387 AC: 408 AN: 1054440

Other (OTH) AF: 0.000228 AC: 13 AN: 57030

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000201 AC: 3 AN: 149394 Hom.: 0 Cov.: 32 AF XY: 0.0000137 AC XY: 1 AN XY: 72772

African (AFR) AF: 0.0000492 AC: 2 AN: 40668

American (AMR) AF: 0.00 AC: 0 AN: 15016

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3458

East Asian (EAS) AF: 0.000195 AC: 1 AN: 5120

South Asian (SAS) AF: 0.00 AC: 0 AN: 4700

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9870

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67290

Other (OTH) AF: 0.00 AC: 0 AN: 2078

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		5.3

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: rs587783876; hg19: chr5-37065069; COSMIC: COSV56943164; COSMIC: COSV56943164;