rs142923613

chr5-36962199-G-A

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 3P and 20B. PM5 PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_133433.4(NIPBL):c.535G>A(p.Ala179Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0032 in 1,613,932 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A179S) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.0034 (6 hom., cov: 32)
  • Exomes 𝑓: 0.0032 (14 hom.)
• Consequence: NIPBL NM_133433.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 7.28

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]

ACMG classification

Verdict is Benign. Variant got -17 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
• PP2: Missense variant where missense usually causes diseases, NIPBL
• BP4: Computational evidence support a benign effect (MetaRNN=0.008623868).
• BP6: Variant 5-36962199-G-A is Benign according to our data. Variant chr5-36962199-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 96343.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-36962199-G-A is described in Lovd as [Pathogenic]. Variant chr5-36962199-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00342 (520/152138) while in subpopulation NFE AF= 0.0034 (231/67996). AF 95% confidence interval is 0.00304. There are 6 homozygotes in gnomad4. There are 338 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 520 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NIPBL	NM_133433.4	c.535G>A	p.Ala179Thr	missense_variant	6/47	ENST00000282516.13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NIPBL	ENST00000282516.13	c.535G>A	p.Ala179Thr	missense_variant	6/47	1	NM_133433.4	P1

Frequencies

GnomAD3 genomes AF: 0.00342 AC: 520 AN: 152020 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.000363

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00144

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0234

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00340

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00384 AC: 966 AN: 251434 Hom.: 6 AF XY: 0.00372 AC XY: 506 AN XY: 135878

Gnomad AFR exome AF: 0.000492

Gnomad AMR exome AF: 0.000809

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000163

Gnomad FIN exome AF: 0.0220

Gnomad NFE exome AF: 0.00380

Gnomad OTH exome AF: 0.00277

GnomAD4 exome AF: 0.00318 AC: 4642 AN: 1461794 Hom.: 14 Cov.: 31 AF XY: 0.00314 AC XY: 2281 AN XY: 727204

Gnomad4 AFR exome AF: 0.000508

Gnomad4 AMR exome AF: 0.000693

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.000174

Gnomad4 FIN exome AF: 0.0202

Gnomad4 NFE exome AF: 0.00299

Gnomad4 OTH exome AF: 0.00286

GnomAD4 genome AF: 0.00342 AC: 520 AN: 152138 Hom.: 6 Cov.: 32 AF XY: 0.00454 AC XY: 338 AN XY: 74378

Gnomad4 AFR AF: 0.000361

Gnomad4 AMR AF: 0.00144

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0234

Gnomad4 NFE AF: 0.00340

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00267 Hom.: 3

Bravo AF: 0.00175

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00311 AC: 12

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00337 AC: 29

ExAC AF: 0.00371 AC: 451

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00289

EpiControl AF: 0.00302

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	NIPBL: PM5, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jan 05, 2017	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 06, 2020	This variant is associated with the following publications: (PMID: 25996639, 21934712) -

Cornelia de Lange syndrome 1 Benign:4

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 18, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Nov 04, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 25, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 09, 2017

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.091	T
BayesDel_noAF	Uncertain	0.10
Cadd	Benign	22
Dann	Uncertain	1.0
DEOGEN2	Benign	0.15	T;.
Eigen	Benign	0.091
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.92	D;D
MetaRNN	Benign	0.0086	T;T
MetaSVM	Uncertain	-0.035	T
MutationAssessor	Benign	-0.56	N;N
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-0.34	N;N
REVEL	Uncertain	0.39
Sift	Benign	0.29	T;T
Sift4G	Benign	0.69	T;T
Polyphen		0.12	B;B
Vest4		0.68
MVP		0.83
MPC		0.26
ClinPred		0.026	T
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.12
gMVP		0.39

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

Publications

LitVar

Other links and lift over

dbSNP: rs142923613; hg19: chr5-36962301; COSMIC: COSV56950282;