5-36971954-T-G

Variant names:

• chr5-36971954-T-G
• rs16903425
• NM_133433.4:c.781T>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.781T>G​(p.Ser261Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00255 in 1,612,812 control chromosomes in the GnomAD database, including 102 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.014 (56 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (46 hom.)
• Consequence: NIPBL NM_133433.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 1.69
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0031066835).
• BP6: Variant 5-36971954-T-G is Benign according to our data. Variant chr5-36971954-T-G is described in ClinVar as Benign. ClinVar VariationId is 159237.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 = 0.014 (2126/152238) while in subpopulation AFR AF = 0.0495 (2055/41552). AF 95% confidence interval is 0.0477. There are 56 homozygotes in GnomAd4. There are 1025 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 2126 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.781T>G	p.Ser261Ala	missense	Exon 8 of 47	NP_597677.2
	NIPBL	NM_001438586.1		c.781T>G	p.Ser261Ala	missense	Exon 8 of 47	NP_001425515.1
	NIPBL	NM_015384.5		c.781T>G	p.Ser261Ala	missense	Exon 8 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.781T>G	p.Ser261Ala	missense	Exon 8 of 47	ENSP00000282516.8
	NIPBL	ENST00000448238.2	TSL:1	c.781T>G	p.Ser261Ala	missense	Exon 8 of 46	ENSP00000406266.2
	NIPBL	ENST00000652901.1		c.781T>G	p.Ser261Ala	missense	Exon 8 of 46	ENSP00000499536.1

Frequencies

GnomAD3 genomes AF: 0.0139 AC: 2115 AN: 152120 Hom.: 55 Cov.: 32

Gnomad AFR AF: 0.0493

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00301

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: 0.0000882

Gnomad OTH AF: 0.00909

GnomAD2 exomes AF: 0.00350 AC: 878 AN: 250974 AF XY: 0.00248

Gnomad AFR exome AF: 0.0507

Gnomad AMR exome AF: 0.00124

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000441

Gnomad OTH exome AF: 0.000981

GnomAD4 exome AF: 0.00136 AC: 1983 AN: 1460574 Hom.: 46 Cov.: 30 AF XY: 0.00120 AC XY: 869 AN XY: 726654

African (AFR) AF: 0.0502 AC: 1677 AN: 33408

American (AMR) AF: 0.00159 AC: 71 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26110

East Asian (EAS) AF: 0.00 AC: 0 AN: 39614

South Asian (SAS) AF: 0.000220 AC: 19 AN: 86200

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53396

Middle Eastern (MID) AF: 0.00139 AC: 8 AN: 5764

European-Non Finnish (NFE) AF: 0.0000153 AC: 17 AN: 1111036

Other (OTH) AF: 0.00317 AC: 191 AN: 60338

GnomAD4 genome AF: 0.0140 AC: 2126 AN: 152238 Hom.: 56 Cov.: 32 AF XY: 0.0138 AC XY: 1025 AN XY: 74430

African (AFR) AF: 0.0495 AC: 2055 AN: 41552

American (AMR) AF: 0.00301 AC: 46 AN: 15294

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

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: 0.0000883 AC: 6 AN: 67986

Other (OTH) AF: 0.00900 AC: 19 AN: 2112

Alfa AF: 0.00519 Hom.: 34

Bravo AF: 0.0157

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0520 AC: 229

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00448 AC: 544

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.14	T
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.017
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.61	T
MetaRNN	Benign	0.0031	T
MetaSVM	Uncertain	-0.24	T
MutationAssessor	Benign	1.4	L
PhyloP100		1.7
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.45	N
REVEL	Benign	0.24
Sift	Benign	0.046	D
Sift4G	Benign	1.0	T
Polyphen		0.019	B
Vest4		0.41
MVP		0.74
MPC		0.17
ClinPred		0.015	T
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.076
gMVP		0.25
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: rs16903425; hg19: chr5-36972056;