chr5-36876834-T-C

Variant names:

• chr5-36876834-T-C
• rs886060552
• NM_133433.4:c.-424T>C

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_133433.4(NIPBL):​c.-424T>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.32 (0 hom., cov: 0)
  • Exomes 𝑓: 0.0044 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: NIPBL NM_133433.4 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.976
• 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-DT (HGNC:51293): (NIPBL divergent transcript)

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).

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.-424T>C		5_prime_UTR	Exon 1 of 47	NP_597677.2
	NIPBL	NM_001438586.1		c.-424T>C		5_prime_UTR	Exon 1 of 47	NP_001425515.1
	NIPBL	NM_015384.5		c.-424T>C		5_prime_UTR	Exon 1 of 46	NP_056199.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NIPBL	ENST00000282516.13	TSL:1 MANE Select	c.-424T>C		5_prime_UTR	Exon 1 of 47	ENSP00000282516.8	Q6KC79-1
	NIPBL	ENST00000448238.2	TSL:1	c.-424T>C		5_prime_UTR	Exon 1 of 46	ENSP00000406266.2	Q6KC79-2
	NIPBL	ENST00000652901.1		c.-424T>C		upstream_gene	N/A	ENSP00000499536.1	A0A590UJS4

Frequencies

GnomAD3 genomes AF: 0.322 AC: 16619 AN: 51672 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.316

Gnomad AMI AF: 0.304

Gnomad AMR AF: 0.260

Gnomad ASJ AF: 0.358

Gnomad EAS AF: 0.285

Gnomad SAS AF: 0.301

Gnomad FIN AF: 0.236

Gnomad MID AF: 0.202

Gnomad NFE AF: 0.349

Gnomad OTH AF: 0.340

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00435 AC: 78 AN: 17922 Hom.: 0 Cov.: 0 AF XY: 0.00366 AC XY: 34 AN XY: 9290

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

African (AFR) AF: 0.00503 AC: 2 AN: 398

American (AMR) AF: 0.00628 AC: 3 AN: 478

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 468

East Asian (EAS) AF: 0.0224 AC: 39 AN: 1738

South Asian (SAS) AF: 0.00298 AC: 1 AN: 336

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 1692

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 88

European-Non Finnish (NFE) AF: 0.00250 AC: 29 AN: 11590

Other (OTH) AF: 0.00353 AC: 4 AN: 1134

⚠️ 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 Data not reliable, filtered out with message: AS_VQSR;InbreedingCoeff AF: 0.322 AC: 16627 AN: 51710 Hom.: 0 Cov.: 0 AF XY: 0.307 AC XY: 7515 AN XY: 24512

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

African (AFR) AF: 0.315 AC: 4392 AN: 13932

American (AMR) AF: 0.260 AC: 1282 AN: 4938

Ashkenazi Jewish (ASJ) AF: 0.358 AC: 454 AN: 1268

East Asian (EAS) AF: 0.284 AC: 343 AN: 1206

South Asian (SAS) AF: 0.302 AC: 355 AN: 1174

European-Finnish (FIN) AF: 0.236 AC: 767 AN: 3248

Middle Eastern (MID) AF: 0.212 AC: 17 AN: 80

European-Non Finnish (NFE) AF: 0.349 AC: 8698 AN: 24896

Other (OTH) AF: 0.338 AC: 246 AN: 728

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	16
DANN	Benign	0.64
PhyloP100		0.98
PromoterAI		-0.11	Neutral
Mutation Taster		=296/4	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: rs886060552; hg19: chr5-36876936;