chr5-36985165-A-G

Variant names:

• chr5-36985165-A-G
• rs140100861
• NM_133433.4:c.1985A>G

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.1985A>G​(p.Lys662Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000795 in 1,613,990 control chromosomes in the GnomAD database, including 26 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K662N) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.00092 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00078 (24 hom.)
• Consequence: NIPBL NM_133433.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 2.57
• Publications: 3 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=0.005590707).
• BP6: Variant 5-36985165-A-G is Benign according to our data. Variant chr5-36985165-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 96331.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000919 (140/152296) while in subpopulation AMR AF = 0.00858 (131/15274). AF 95% confidence interval is 0.00738. There are 2 homozygotes in GnomAd4. There are 62 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 140 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.1985A>G	p.Lys662Arg	missense	Exon 10 of 47	NP_597677.2
	NIPBL	NM_001438586.1		c.1985A>G	p.Lys662Arg	missense	Exon 10 of 47	NP_001425515.1
	NIPBL	NM_015384.5		c.1985A>G	p.Lys662Arg	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.1985A>G	p.Lys662Arg	missense	Exon 10 of 47	ENSP00000282516.8	Q6KC79-1
	NIPBL	ENST00000448238.2	TSL:1	c.1985A>G	p.Lys662Arg	missense	Exon 10 of 46	ENSP00000406266.2	Q6KC79-2
	NIPBL	ENST00000652901.1		c.1985A>G	p.Lys662Arg	missense	Exon 10 of 46	ENSP00000499536.1	A0A590UJS4

Frequencies

GnomAD3 genomes AF: 0.000920 AC: 140 AN: 152178 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00859

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.00399 AC: 1000 AN: 250624 AF XY: 0.00294

Gnomad AFR exome AF: 0.000247

Gnomad AMR exome AF: 0.0287

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000883

Gnomad OTH exome AF: 0.00115

GnomAD4 exome AF: 0.000782 AC: 1143 AN: 1461694 Hom.: 24 Cov.: 32 AF XY: 0.000635 AC XY: 462 AN XY: 727138

African (AFR) AF: 0.000149 AC: 5 AN: 33468

American (AMR) AF: 0.0249 AC: 1110 AN: 44624

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

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39698

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53406

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

European-Non Finnish (NFE) AF: 0.00000719 AC: 8 AN: 1111950

Other (OTH) AF: 0.000315 AC: 19 AN: 60396

GnomAD4 genome AF: 0.000919 AC: 140 AN: 152296 Hom.: 2 Cov.: 32 AF XY: 0.000832 AC XY: 62 AN XY: 74480

African (AFR) AF: 0.000192 AC: 8 AN: 41580

American (AMR) AF: 0.00858 AC: 131 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68016

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.000363 Hom.: 2

Bravo AF: 0.00223

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00314 AC: 381

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Cornelia de Lange syndrome 1 (3)
-	-	3	not provided (3)
-	-	2	not specified (2)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	15
DANN	Uncertain	0.99
DEOGEN2	Benign	0.16	T
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.18
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.69	T
MetaRNN	Benign	0.0056	T
MetaSVM	Benign	-0.30	T
MutationAssessor	Benign	1.8	L
PhyloP100		2.6
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.31	N
REVEL	Benign	0.22
Sift	Benign	0.21	T
Sift4G	Benign	0.27	T
Polyphen		0.0	B
Vest4		0.049
MVP		0.66
MPC		0.20
ClinPred		0.017	T
GERP RS		4.8
Varity_R		0.037
gMVP		0.41
Mutation Taster		=99/1	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: rs140100861; hg19: chr5-36985267;