rs61748200

Variant names:

• chr5-37036390-C-T
• rs61748200
• NM_133433.4:c.5874C>T

Your query was ambiguous. Multiple possible variants found:

• chr5-37036390-C-T
• chr5-37036390-C-A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_133433.4(NIPBL):​c.5874C>T​(p.Ser1958Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.143 in 1,272,910 control chromosomes in the GnomAD database, including 14,646 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (1650 hom., cov: 27)
  • Exomes 𝑓: 0.14 (12996 hom.)
• Consequence: NIPBL NM_133433.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -1.66
• Publications: 10 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BP6: Variant 5-37036390-C-T is Benign according to our data. Variant chr5-37036390-C-T is described in ClinVar as Benign. ClinVar VariationId is 96348.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.66 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.305 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.5874C>T	p.Ser1958Ser	synonymous	Exon 33 of 47	NP_597677.2
	NIPBL	NM_001438586.1		c.5874C>T	p.Ser1958Ser	synonymous	Exon 33 of 47	NP_001425515.1
	NIPBL	NM_015384.5		c.5874C>T	p.Ser1958Ser	synonymous	Exon 33 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.5874C>T	p.Ser1958Ser	synonymous	Exon 33 of 47	ENSP00000282516.8	Q6KC79-1
	NIPBL	ENST00000448238.2	TSL:1	c.5874C>T	p.Ser1958Ser	synonymous	Exon 33 of 46	ENSP00000406266.2	Q6KC79-2
	NIPBL	ENST00000652901.1		c.5874C>T	p.Ser1958Ser	synonymous	Exon 33 of 46	ENSP00000499536.1	A0A590UJS4

Frequencies

GnomAD3 genomes AF: 0.138 AC: 19486 AN: 141628 Hom.: 1653 Cov.: 27

Gnomad AFR AF: 0.0544

Gnomad AMI AF: 0.161

Gnomad AMR AF: 0.127

Gnomad ASJ AF: 0.191

Gnomad EAS AF: 0.318

Gnomad SAS AF: 0.254

Gnomad FIN AF: 0.183

Gnomad MID AF: 0.170

Gnomad NFE AF: 0.157

Gnomad OTH AF: 0.151

GnomAD2 exomes AF: 0.151 AC: 17008 AN: 112882 AF XY: 0.158

Gnomad AFR exome AF: 0.0371

Gnomad AMR exome AF: 0.0906

Gnomad ASJ exome AF: 0.178

Gnomad EAS exome AF: 0.256

Gnomad FIN exome AF: 0.166

Gnomad NFE exome AF: 0.139

Gnomad OTH exome AF: 0.124

GnomAD4 exome AF: 0.144 AC: 163069 AN: 1131282 Hom.: 12996 Cov.: 16 AF XY: 0.148 AC XY: 82448 AN XY: 558642

African (AFR) AF: 0.0417 AC: 1024 AN: 24552

American (AMR) AF: 0.0988 AC: 2127 AN: 21530

Ashkenazi Jewish (ASJ) AF: 0.178 AC: 3445 AN: 19404

East Asian (EAS) AF: 0.288 AC: 8025 AN: 27882

South Asian (SAS) AF: 0.222 AC: 9953 AN: 44914

European-Finnish (FIN) AF: 0.163 AC: 6287 AN: 38564

Middle Eastern (MID) AF: 0.152 AC: 485 AN: 3188

European-Non Finnish (NFE) AF: 0.138 AC: 125115 AN: 905980

Other (OTH) AF: 0.146 AC: 6608 AN: 45268

GnomAD4 genome AF: 0.137 AC: 19473 AN: 141628 Hom.: 1650 Cov.: 27 AF XY: 0.142 AC XY: 9757 AN XY: 68470

African (AFR) AF: 0.0542 AC: 2057 AN: 37952

American (AMR) AF: 0.127 AC: 1778 AN: 13960

Ashkenazi Jewish (ASJ) AF: 0.191 AC: 657 AN: 3432

East Asian (EAS) AF: 0.318 AC: 1566 AN: 4920

South Asian (SAS) AF: 0.253 AC: 1155 AN: 4564

European-Finnish (FIN) AF: 0.183 AC: 1384 AN: 7580

Middle Eastern (MID) AF: 0.177 AC: 46 AN: 260

European-Non Finnish (NFE) AF: 0.157 AC: 10389 AN: 66134

Other (OTH) AF: 0.154 AC: 296 AN: 1926

Alfa AF: 0.138 Hom.: 807

Bravo AF: 0.127

Asia WGS AF: 0.247 AC: 843 AN: 3416

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
CADD	Benign	2.6
DANN	Benign	0.48
PhyloP100		-1.7
Mutation Taster		=97/3	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs61748200; hg19: chr5-37036492; COSMIC: COSV105175506;