rs3822471

Positions:

• chr5-36985201-A-G

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

The NM_133433.4(NIPBL):​c.2021A>G​(p.Asn674Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.118 in 1,613,756 control chromosomes in the GnomAD database, including 12,088 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (1225 hom., cov: 32)
  • Exomes 𝑓: 0.12 (10863 hom.)
• Consequence: NIPBL NM_133433.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.597

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 -19 ACMG points.

• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), NIPBL. . Gene score misZ 5.5737 (greater than the threshold 3.09). Trascript score misZ 6.6817 (greater than threshold 3.09). GenCC has associacion of gene with Cornelia de Lange syndrome, Cornelia de Lange syndrome 1.
• BP4: Computational evidence support a benign effect (MetaRNN=0.0011794567).
• BP6: Variant 5-36985201-A-G is Benign according to our data. Variant chr5-36985201-A-G is described in ClinVar as [Benign]. Clinvar id is 96333.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-36985201-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.183 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NIPBL	NM_133433.4	c.2021A>G	p.Asn674Ser	missense_variant	10/47	ENST00000282516.13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NIPBL	ENST00000282516.13	c.2021A>G	p.Asn674Ser	missense_variant	10/47	1	NM_133433.4	P1
NIPBL	ENST00000448238.2	c.2021A>G	p.Asn674Ser	missense_variant	10/46	1
NIPBL	ENST00000652901.1	c.2021A>G	p.Asn674Ser	missense_variant	10/46
NIPBL	ENST00000504430.5	n.1641A>G		non_coding_transcript_exon_variant	6/8	2

Frequencies

GnomAD3 genomes AF: 0.122 AC: 18554 AN: 151998 Hom.: 1222 Cov.: 32

Gnomad AFR AF: 0.0980

Gnomad AMI AF: 0.0516

Gnomad AMR AF: 0.189

Gnomad ASJ AF: 0.203

Gnomad EAS AF: 0.128

Gnomad SAS AF: 0.117

Gnomad FIN AF: 0.132

Gnomad MID AF: 0.139

Gnomad NFE AF: 0.116

Gnomad OTH AF: 0.149

GnomAD3 exomes AF: 0.137 AC: 34363 AN: 250244 Hom.: 2603 AF XY: 0.133 AC XY: 17939 AN XY: 135372

Gnomad AFR exome AF: 0.0923

Gnomad AMR exome AF: 0.234

Gnomad ASJ exome AF: 0.210

Gnomad EAS exome AF: 0.127

Gnomad SAS exome AF: 0.110

Gnomad FIN exome AF: 0.127

Gnomad NFE exome AF: 0.118

Gnomad OTH exome AF: 0.145

GnomAD4 exome AF: 0.118 AC: 172650 AN: 1461640 Hom.: 10863 Cov.: 33 AF XY: 0.118 AC XY: 85718 AN XY: 727116

Gnomad4 AFR exome AF: 0.0979

Gnomad4 AMR exome AF: 0.227

Gnomad4 ASJ exome AF: 0.208

Gnomad4 EAS exome AF: 0.101

Gnomad4 SAS exome AF: 0.109

Gnomad4 FIN exome AF: 0.127

Gnomad4 NFE exome AF: 0.112

Gnomad4 OTH exome AF: 0.128

GnomAD4 genome AF: 0.122 AC: 18580 AN: 152116 Hom.: 1225 Cov.: 32 AF XY: 0.125 AC XY: 9301 AN XY: 74348

Gnomad4 AFR AF: 0.0980

Gnomad4 AMR AF: 0.189

Gnomad4 ASJ AF: 0.203

Gnomad4 EAS AF: 0.127

Gnomad4 SAS AF: 0.118

Gnomad4 FIN AF: 0.132

Gnomad4 NFE AF: 0.116

Gnomad4 OTH AF: 0.153

Alfa AF: 0.125 Hom.: 3091

Bravo AF: 0.126

TwinsUK AF: 0.107 AC: 398

ALSPAC AF: 0.102 AC: 394

ESP6500AA AF: 0.0921 AC: 406

ESP6500EA AF: 0.125 AC: 1074

ExAC AF: 0.131 AC: 15954

Asia WGS AF: 0.169 AC: 585 AN: 3478

EpiCase AF: 0.132

EpiControl AF: 0.129

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 02, 2014	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Cornelia de Lange syndrome 1 Benign:4

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
Benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 15, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 07, 2018	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 11, 2016

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	0.095
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	5.8
DANN	Benign	0.76
DEOGEN2	Benign	0.17	T;.
Eigen	Benign	-0.69
Eigen_PC	Benign	-0.54
FATHMM_MKL	Benign	0.47	N
LIST_S2	Benign	0.74	T;T
MetaRNN	Benign	0.0012	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	L;L
MutationTaster	Benign	0.59	P;P
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.68	N;N
REVEL	Benign	0.23
Sift	Benign	0.18	T;T
Sift4G	Benign	0.56	T;T
Polyphen		0.0	B;B
Vest4		0.031
MPC		0.15
ClinPred		0.0018	T
GERP RS		2.3
Varity_R		0.026
gMVP		0.21

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: rs3822471; hg19: chr5-36985303; COSMIC: COSV56947629;