chr5-37036347-G-GTATA

Variant names:

• chr5-37036347-G-GTATA
• rs10554564
• NM_133433.4:c.5863-14_5863-11dupATAT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_133433.4(NIPBL):​c.5863-14_5863-11dupATAT variant causes a intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.031 (208 hom., cov: 0)
  • Exomes 𝑓: 0.0019 (3 hom.)
• Consequence: NIPBL NM_133433.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0120
• Publications: 2 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 -16 ACMG points.

• BP6: Variant 5-37036347-G-GTATA is Benign according to our data. Variant chr5-37036347-G-GTATA is described in ClinVar as Benign. ClinVar VariationId is 167360.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.104 is higher than 0.05.

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.5863-14_5863-11dupATAT		intron	N/A	NP_597677.2
	NIPBL	NM_001438586.1		c.5863-14_5863-11dupATAT		intron	N/A	NP_001425515.1
	NIPBL	NM_015384.5		c.5863-14_5863-11dupATAT		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.5863-32_5863-31insTATA		intron	N/A	ENSP00000282516.8	Q6KC79-1
	NIPBL	ENST00000448238.2	TSL:1	c.5863-32_5863-31insTATA		intron	N/A	ENSP00000406266.2	Q6KC79-2
	NIPBL	ENST00000652901.1		c.5863-32_5863-31insTATA		intron	N/A	ENSP00000499536.1	A0A590UJS4

Frequencies

GnomAD3 genomes AF: 0.0308 AC: 4182 AN: 135944 Hom.: 206 Cov.: 0

Gnomad AFR AF: 0.107

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0130

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000211

Gnomad SAS AF: 0.00116

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00345

Gnomad NFE AF: 0.000313

Gnomad OTH AF: 0.0240

GnomAD2 exomes AF: 0.00189 AC: 62 AN: 32888 AF XY: 0.00122

Gnomad AFR exome AF: 0.121

Gnomad AMR exome AF: 0.00506

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000135

Gnomad NFE exome AF: 0.000535

Gnomad OTH exome AF: 0.00157

GnomAD4 exome AF: 0.00194 AC: 482 AN: 248048 Hom.: 3 Cov.: 0 AF XY: 0.00176 AC XY: 238 AN XY: 135454

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0607 AC: 263 AN: 4336

American (AMR) AF: 0.00635 AC: 33 AN: 5196

Ashkenazi Jewish (ASJ) AF: 0.000150 AC: 1 AN: 6674

East Asian (EAS) AF: 0.000513 AC: 5 AN: 9756

South Asian (SAS) AF: 0.00156 AC: 16 AN: 10254

European-Finnish (FIN) AF: 0.000286 AC: 6 AN: 20992

Middle Eastern (MID) AF: 0.00233 AC: 2 AN: 858

European-Non Finnish (NFE) AF: 0.000547 AC: 98 AN: 179024

Other (OTH) AF: 0.00529 AC: 58 AN: 10958

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0308 AC: 4184 AN: 135938 Hom.: 208 Cov.: 0 AF XY: 0.0302 AC XY: 1968 AN XY: 65236

African (AFR) AF: 0.107 AC: 3941 AN: 36754

American (AMR) AF: 0.0129 AC: 172 AN: 13332

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3314

East Asian (EAS) AF: 0.000212 AC: 1 AN: 4724

South Asian (SAS) AF: 0.00117 AC: 5 AN: 4286

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6690

Middle Eastern (MID) AF: 0.00370 AC: 1 AN: 270

European-Non Finnish (NFE) AF: 0.000313 AC: 20 AN: 63860

Other (OTH) AF: 0.0239 AC: 44 AN: 1844

Alfa AF: 0.00 Hom.: 457

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.012
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs10554564; hg19: chr5-37036449;