rs185678374

Variant names:

• chr5-36985474-G-A
• rs185678374
• NM_133433.4:c.2294G>A

Your query was ambiguous. Multiple possible variants found:

• chr5-36985474-G-A
• chr5-36985474-G-C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_133433.4(NIPBL):​c.2294G>A​(p.Arg765Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00065 in 1,613,722 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R765T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00059 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00066 (2 hom.)
• Consequence: NIPBL NM_133433.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:10
• Conservation: PhyloP100: 3.11
• Publications: 8 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.013206512).
• BP6: Variant 5-36985474-G-A is Benign according to our data. Variant chr5-36985474-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 159051.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000591 (90/152172) while in subpopulation NFE AF = 0.00107 (73/68010). AF 95% confidence interval is 0.000875. There are 0 homozygotes in GnomAd4. There are 46 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 90 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NIPBL	NM_133433.4	MANE Select	c.2294G>A	p.Arg765Lys	missense	Exon 10 of 47	NP_597677.2
	NIPBL	NM_001438586.1		c.2294G>A	p.Arg765Lys	missense	Exon 10 of 47	NP_001425515.1
	NIPBL	NM_015384.5		c.2294G>A	p.Arg765Lys	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.2294G>A	p.Arg765Lys	missense	Exon 10 of 47	ENSP00000282516.8	Q6KC79-1
	NIPBL	ENST00000448238.2	TSL:1	c.2294G>A	p.Arg765Lys	missense	Exon 10 of 46	ENSP00000406266.2	Q6KC79-2
	NIPBL	ENST00000652901.1		c.2294G>A	p.Arg765Lys	missense	Exon 10 of 46	ENSP00000499536.1	A0A590UJS4

Frequencies

GnomAD3 genomes AF: 0.000592 AC: 90 AN: 152054 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00107

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000521 AC: 130 AN: 249308 AF XY: 0.000540

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000581

Gnomad ASJ exome AF: 0.00190

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000277

Gnomad NFE exome AF: 0.000873

Gnomad OTH exome AF: 0.000821

GnomAD4 exome AF: 0.000656 AC: 959 AN: 1461550 Hom.: 2 Cov.: 32 AF XY: 0.000657 AC XY: 478 AN XY: 727060

African (AFR) AF: 0.000120 AC: 4 AN: 33470

American (AMR) AF: 0.0000896 AC: 4 AN: 44640

Ashkenazi Jewish (ASJ) AF: 0.00237 AC: 62 AN: 26130

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.000319 AC: 17 AN: 53242

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000753 AC: 837 AN: 1111954

Other (OTH) AF: 0.000580 AC: 35 AN: 60394

GnomAD4 genome AF: 0.000591 AC: 90 AN: 152172 Hom.: 0 Cov.: 32 AF XY: 0.000618 AC XY: 46 AN XY: 74398

African (AFR) AF: 0.0000241 AC: 1 AN: 41510

American (AMR) AF: 0.00 AC: 0 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.00346 AC: 12 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.000377 AC: 4 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00107 AC: 73 AN: 68010

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.000896 Hom.: 0

Bravo AF: 0.000491

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000814 AC: 7

ExAC AF: 0.000552 AC: 67

EpiCase AF: 0.000546

EpiControl AF: 0.000771

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.13
CADD	Benign	20
DANN	Benign	0.95
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.11
Eigen_PC	Benign	0.15
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.68	T
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.013	T
MetaSVM	Uncertain	0.0032	D
MutationAssessor	Benign	-0.090	N
PhyloP100		3.1
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-0.13	N
REVEL	Uncertain	0.30
Sift	Benign	0.35	T
Sift4G	Benign	0.99	T
Polyphen		0.0010	B
Vest4		0.33
MVP		0.61
MPC		0.19
ClinPred		0.030	T
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.13
gMVP		0.22
Mutation Taster		=88/12	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: rs185678374; hg19: chr5-36985576;