rs145778995

Variant names:

• chr5-37044344-T-C
• rs145778995
• NM_133433.4:c.6109-3T>C

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.6109-3T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00545 in 1,613,020 control chromosomes in the GnomAD database, including 35 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0036 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0056 (31 hom.)
• Consequence: NIPBL NM_133433.4 splice_region, intron
• Scores: Splicing: ADA: 0.00006533
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: -0.0820
• Publications: 6 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 (BayesDel_noAF=-0.83).
• BP6: Variant 5-37044344-T-C is Benign according to our data. Variant chr5-37044344-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 96349.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00362 (551/152324) while in subpopulation SAS AF = 0.00538 (26/4834). AF 95% confidence interval is 0.00483. There are 4 homozygotes in GnomAd4. There are 270 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 551 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.6109-3T>C		splice_region intron	N/A	NP_597677.2
	NIPBL	NM_001438586.1		c.6109-3T>C		splice_region intron	N/A	NP_001425515.1
	NIPBL	NM_015384.5		c.6109-3T>C		splice_region intron	N/A	NP_056199.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NIPBL	ENST00000282516.13	TSL:1 MANE Select	c.6109-3T>C		splice_region intron	N/A	ENSP00000282516.8	Q6KC79-1
	NIPBL	ENST00000448238.2	TSL:1	c.6109-3T>C		splice_region intron	N/A	ENSP00000406266.2	Q6KC79-2
	NIPBL	ENST00000652901.1		c.6109-3T>C		splice_region intron	N/A	ENSP00000499536.1	A0A590UJS4

Frequencies

GnomAD3 genomes AF: 0.00362 AC: 551 AN: 152206 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.000989

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00491

Gnomad ASJ AF: 0.00490

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00537

Gnomad FIN AF: 0.00226

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00528

Gnomad OTH AF: 0.00430

GnomAD2 exomes AF: 0.00413 AC: 1034 AN: 250088 AF XY: 0.00437

Gnomad AFR exome AF: 0.00107

Gnomad AMR exome AF: 0.00203

Gnomad ASJ exome AF: 0.00726

Gnomad EAS exome AF: 0.0000546

Gnomad FIN exome AF: 0.00148

Gnomad NFE exome AF: 0.00580

Gnomad OTH exome AF: 0.00444

GnomAD4 exome AF: 0.00564 AC: 8243 AN: 1460696 Hom.: 31 Cov.: 30 AF XY: 0.00577 AC XY: 4194 AN XY: 726682

African (AFR) AF: 0.000807 AC: 27 AN: 33458

American (AMR) AF: 0.00174 AC: 78 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00678 AC: 177 AN: 26114

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39620

South Asian (SAS) AF: 0.00538 AC: 464 AN: 86226

European-Finnish (FIN) AF: 0.00236 AC: 126 AN: 53292

Middle Eastern (MID) AF: 0.00278 AC: 16 AN: 5758

European-Non Finnish (NFE) AF: 0.00635 AC: 7056 AN: 1111182

Other (OTH) AF: 0.00489 AC: 295 AN: 60338

GnomAD4 genome AF: 0.00362 AC: 551 AN: 152324 Hom.: 4 Cov.: 32 AF XY: 0.00362 AC XY: 270 AN XY: 74496

African (AFR) AF: 0.000986 AC: 41 AN: 41572

American (AMR) AF: 0.00490 AC: 75 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00490 AC: 17 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00538 AC: 26 AN: 4834

European-Finnish (FIN) AF: 0.00226 AC: 24 AN: 10614

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

European-Non Finnish (NFE) AF: 0.00528 AC: 359 AN: 68028

Other (OTH) AF: 0.00425 AC: 9 AN: 2116

Alfa AF: 0.00532 Hom.: 4

Bravo AF: 0.00376

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00529

EpiControl AF: 0.00534

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not provided (6)
-	-	5	Cornelia de Lange syndrome 1 (5)
-	-	2	not specified (2)
-	-	1	Inborn genetic diseases (1)
-	-	1	NIPBL-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.48
DANN	Benign	0.45
PhyloP100		-0.082
Mutation Taster		=78/22	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000065
dbscSNV1_RF	Benign	0.010
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: rs145778995; hg19: chr5-37044446;