5-36985145-G-T

Variant names:

• chr5-36985145-G-T
• rs80358350
• NM_133433.4:c.1965G>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_133433.4(NIPBL):​c.1965G>T​(p.Glu655Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00064 in 1,613,842 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0035 (3 hom., cov: 32)
  • Exomes 𝑓: 0.00034 (5 hom.)
• Consequence: NIPBL NM_133433.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.589
• Publications: 4 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=0.0042012334).
• BP6: Variant 5-36985145-G-T is Benign according to our data. Variant chr5-36985145-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 99924.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00349 (531/152200) while in subpopulation AFR AF = 0.012 (500/41546). AF 95% confidence interval is 0.0112. There are 3 homozygotes in GnomAd4. There are 255 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 531 AD gene.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NIPBL	NM_133433.4	MANE Select	c.1965G>T	p.Glu655Asp	missense	Exon 10 of 47	NP_597677.2
	NIPBL	NM_001438586.1		c.1965G>T	p.Glu655Asp	missense	Exon 10 of 47	NP_001425515.1
	NIPBL	NM_015384.5		c.1965G>T	p.Glu655Asp	missense	Exon 10 of 46	NP_056199.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NIPBL	ENST00000282516.13	TSL:1 MANE Select	c.1965G>T	p.Glu655Asp	missense	Exon 10 of 47	ENSP00000282516.8
	NIPBL	ENST00000448238.2	TSL:1	c.1965G>T	p.Glu655Asp	missense	Exon 10 of 46	ENSP00000406266.2
	NIPBL	ENST00000652901.1		c.1965G>T	p.Glu655Asp	missense	Exon 10 of 46	ENSP00000499536.1

Frequencies

GnomAD3 genomes AF: 0.00343 AC: 522 AN: 152082 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.0119

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: 0.00

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.000854 AC: 214 AN: 250614 AF XY: 0.000701

Gnomad AFR exome AF: 0.0112

Gnomad AMR exome AF: 0.000697

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000343 AC: 502 AN: 1461642 Hom.: 5 Cov.: 32 AF XY: 0.000319 AC XY: 232 AN XY: 727114

African (AFR) AF: 0.0118 AC: 395 AN: 33464

American (AMR) AF: 0.000762 AC: 34 AN: 44634

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.000128 AC: 11 AN: 86246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53400

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5766

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1111912

Other (OTH) AF: 0.000894 AC: 54 AN: 60396

GnomAD4 genome AF: 0.00349 AC: 531 AN: 152200 Hom.: 3 Cov.: 32 AF XY: 0.00343 AC XY: 255 AN XY: 74420

African (AFR) AF: 0.0120 AC: 500 AN: 41546

American (AMR) AF: 0.00144 AC: 22 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

Middle Eastern (MID) AF: 0.00342 AC: 1 AN: 292

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67998

Other (OTH) AF: 0.00331 AC: 7 AN: 2112

Alfa AF: 0.00130 Hom.: 2

Bravo AF: 0.00396

ESP6500AA AF: 0.0141 AC: 62

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00103 AC: 125

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 02, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 28, 2014

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 13, 2014

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

Cornelia de Lange syndrome 1 Benign:4

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Jan 28, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jul 15, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Sep 16, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Inborn genetic diseases Benign:1

Aug 30, 2016

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	13
DANN	Uncertain	0.98
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.70
Eigen_PC	Benign	-0.53
FATHMM_MKL	Benign	0.52	D
LIST_S2	Benign	0.70	T
MetaRNN	Benign	0.0042	T
MetaSVM	Uncertain	-0.19	T
MutationAssessor	Benign	1.5	L
PhyloP100		0.59
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.32	N
REVEL	Benign	0.22
Sift	Benign	0.10	T
Sift4G	Benign	0.32	T
Polyphen		0.0	B
Vest4		0.12
MutPred		0.13		Loss of methylation at K652 (P = 0.084)
MVP		0.49
MPC		0.17
ClinPred		0.0022	T
GERP RS		2.9
Varity_R		0.043
gMVP		0.36
Mutation Taster		=97/3	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: rs80358350; hg19: chr5-36985247;