rs540966156

Variant names:

• chr5-36876946-T-A
• rs540966156
• NM_133433.4:c.-312T>A

Your query was ambiguous. Multiple possible variants found:

• chr5-36876946-T-A
• chr5-36876946-T-G

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_133433.4(NIPBL):​c.-312T>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00372 in 347,926 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0029 (4 hom., cov: 29)
  • Exomes 𝑓: 0.0043 (2 hom.)
• Consequence: NIPBL NM_133433.4 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.15
• Publications: 0 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-DT (HGNC:51293): (NIPBL divergent transcript)

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.38).
• BP6: Variant 5-36876946-T-A is Benign according to our data. Variant chr5-36876946-T-A is described in ClinVar as Likely_benign. ClinVar VariationId is 353366.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 = 0.00288 (429/148726) while in subpopulation AMR AF = 0.00498 (75/15064). AF 95% confidence interval is 0.00407. There are 4 homozygotes in GnomAd4. There are 198 alleles in the male GnomAd4 subpopulation. Median coverage is 29. This position passed quality control check.
• BS2: High AC in GnomAd4 at 429 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.-312T>A		5_prime_UTR	Exon 1 of 47	NP_597677.2
	NIPBL	NM_001438586.1		c.-312T>A		5_prime_UTR	Exon 1 of 47	NP_001425515.1
	NIPBL	NM_015384.5		c.-312T>A		5_prime_UTR	Exon 1 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.-312T>A		5_prime_UTR	Exon 1 of 47	ENSP00000282516.8	Q6KC79-1
	NIPBL	ENST00000448238.2	TSL:1	c.-312T>A		5_prime_UTR	Exon 1 of 46	ENSP00000406266.2	Q6KC79-2
	NIPBL	ENST00000652901.1		c.-312T>A		5_prime_UTR	Exon 1 of 46	ENSP00000499536.1	A0A590UJS4

Frequencies

GnomAD3 genomes AF: 0.00287 AC: 427 AN: 148640 Hom.: 4 Cov.: 29

Gnomad AFR AF: 0.000820

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00499

Gnomad ASJ AF: 0.00989

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00304

Gnomad FIN AF: 0.0000995

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00392

Gnomad OTH AF: 0.00342

GnomAD4 exome AF: 0.00434 AC: 864 AN: 199200 Hom.: 2 Cov.: 0 AF XY: 0.00456 AC XY: 465 AN XY: 101862

African (AFR) AF: 0.00113 AC: 6 AN: 5324

American (AMR) AF: 0.00252 AC: 15 AN: 5958

Ashkenazi Jewish (ASJ) AF: 0.00953 AC: 68 AN: 7136

East Asian (EAS) AF: 0.00 AC: 0 AN: 18544

South Asian (SAS) AF: 0.00539 AC: 14 AN: 2598

European-Finnish (FIN) AF: 0.000271 AC: 5 AN: 18452

Middle Eastern (MID) AF: 0.0175 AC: 18 AN: 1028

European-Non Finnish (NFE) AF: 0.00533 AC: 678 AN: 127214

Other (OTH) AF: 0.00463 AC: 60 AN: 12946

GnomAD4 genome AF: 0.00288 AC: 429 AN: 148726 Hom.: 4 Cov.: 29 AF XY: 0.00273 AC XY: 198 AN XY: 72526

African (AFR) AF: 0.000818 AC: 33 AN: 40344

American (AMR) AF: 0.00498 AC: 75 AN: 15064

Ashkenazi Jewish (ASJ) AF: 0.00989 AC: 34 AN: 3438

East Asian (EAS) AF: 0.00 AC: 0 AN: 4850

South Asian (SAS) AF: 0.00348 AC: 16 AN: 4594

European-Finnish (FIN) AF: 0.0000995 AC: 1 AN: 10046

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 276

European-Non Finnish (NFE) AF: 0.00392 AC: 263 AN: 67148

Other (OTH) AF: 0.00339 AC: 7 AN: 2066

Alfa AF: 0.00254 Hom.: 1

Bravo AF: 0.00258

Asia WGS AF: 0.00260 AC: 9 AN: 3476

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Cornelia de Lange syndrome 1 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.38
CADD	Benign	19
DANN	Benign	0.91
PhyloP100		2.1
PromoterAI		0.34	Neutral
Mutation Taster		=298/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs540966156; hg19: chr5-36877048;