rs3822471

Variant names:

• chr5-36985201-A-G
• rs3822471
• NM_133433.4:c.2021A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. 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. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N674H) has been classified as Uncertain significance.

• 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:12
• Conservation: PhyloP100: 0.597
• Publications: 28 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 -20 ACMG points.

• 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 VariationId is 96333.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.183 is higher than 0.05.

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.2021A>G	p.Asn674Ser	missense	Exon 10 of 47	NP_597677.2
	NIPBL	NM_001438586.1		c.2021A>G	p.Asn674Ser	missense	Exon 10 of 47	NP_001425515.1
	NIPBL	NM_015384.5		c.2021A>G	p.Asn674Ser	missense	Exon 10 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.2021A>G	p.Asn674Ser	missense	Exon 10 of 47	ENSP00000282516.8	Q6KC79-1
	NIPBL	ENST00000448238.2	TSL:1	c.2021A>G	p.Asn674Ser	missense	Exon 10 of 46	ENSP00000406266.2	Q6KC79-2
	NIPBL	ENST00000652901.1		c.2021A>G	p.Asn674Ser	missense	Exon 10 of 46	ENSP00000499536.1	A0A590UJS4

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

GnomAD2 exomes AF: 0.137 AC: 34363 AN: 250244 AF XY: 0.133

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 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

African (AFR) AF: 0.0979 AC: 3275 AN: 33458

American (AMR) AF: 0.227 AC: 10142 AN: 44626

Ashkenazi Jewish (ASJ) AF: 0.208 AC: 5444 AN: 26130

East Asian (EAS) AF: 0.101 AC: 4019 AN: 39694

South Asian (SAS) AF: 0.109 AC: 9378 AN: 86252

European-Finnish (FIN) AF: 0.127 AC: 6786 AN: 53392

Middle Eastern (MID) AF: 0.166 AC: 957 AN: 5768

European-Non Finnish (NFE) AF: 0.112 AC: 124907 AN: 1111928

Other (OTH) AF: 0.128 AC: 7742 AN: 60392

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

African (AFR) AF: 0.0980 AC: 4068 AN: 41510

American (AMR) AF: 0.189 AC: 2882 AN: 15242

Ashkenazi Jewish (ASJ) AF: 0.203 AC: 703 AN: 3468

East Asian (EAS) AF: 0.127 AC: 660 AN: 5180

South Asian (SAS) AF: 0.118 AC: 567 AN: 4818

European-Finnish (FIN) AF: 0.132 AC: 1402 AN: 10592

Middle Eastern (MID) AF: 0.150 AC: 44 AN: 294

European-Non Finnish (NFE) AF: 0.116 AC: 7884 AN: 67988

Other (OTH) AF: 0.153 AC: 323 AN: 2114

Alfa AF: 0.122 Hom.: 5495

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	Cornelia de Lange syndrome 1 (4)
-	-	4	not specified (4)
-	-	3	not provided (3)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

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
MetaRNN	Benign	0.0012	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	L
PhyloP100		0.60
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.68	N
REVEL	Benign	0.23
Sift	Benign	0.18	T
Sift4G	Benign	0.56	T
Polyphen		0.0	B
Vest4		0.031
MPC		0.15
ClinPred		0.0018	T
GERP RS		2.3
Varity_R		0.026
gMVP		0.21
Mutation Taster		=98/2	polymorphism (auto)

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