rs200333487

Positions:

• chr8-116854479-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_006265.3(RAD21):​c.938-11T>C variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0053 in 1,595,000 control chromosomes in the GnomAD database, including 34 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0040 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0054 (31 hom.)
• Consequence: RAD21 NM_006265.3 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.001232
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.71

Genes affected

RAD21 (HGNC:9811): (RAD21 cohesin complex component) The protein encoded by this gene is highly similar to the gene product of Schizosaccharomyces pombe rad21, a gene involved in the repair of DNA double-strand breaks, as well as in chromatid cohesion during mitosis. This protein is a nuclear phospho-protein, which becomes hyperphosphorylated in cell cycle M phase. The highly regulated association of this protein with mitotic chromatin specifically at the centromere region suggests its role in sister chromatid cohesion in mitotic cells. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 8-116854479-A-G is Benign according to our data. Variant chr8-116854479-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 159809.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-116854479-A-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00397 (605/152248) while in subpopulation NFE AF= 0.00763 (519/68006). AF 95% confidence interval is 0.00709. There are 3 homozygotes in gnomad4. There are 256 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RAD21	NM_006265.3	c.938-11T>C		splice_polypyrimidine_tract_variant, intron_variant		ENST00000297338.7	NP_006256.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RAD21	ENST00000297338.7	c.938-11T>C		splice_polypyrimidine_tract_variant, intron_variant		1	NM_006265.3	ENSP00000297338	P1

Frequencies

GnomAD3 genomes AF: 0.00398 AC: 605 AN: 152132 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.000893

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.000785

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00151

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00763

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00373 AC: 932 AN: 249888 Hom.: 4 AF XY: 0.00357 AC XY: 482 AN XY: 135134

Gnomad AFR exome AF: 0.000678

Gnomad AMR exome AF: 0.000961

Gnomad ASJ exome AF: 0.00481

Gnomad EAS exome AF: 0.0000545

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00279

Gnomad NFE exome AF: 0.00677

Gnomad OTH exome AF: 0.00248

GnomAD4 exome AF: 0.00544 AC: 7847 AN: 1442752 Hom.: 31 Cov.: 29 AF XY: 0.00529 AC XY: 3802 AN XY: 719142

Gnomad4 AFR exome AF: 0.000790

Gnomad4 AMR exome AF: 0.00110

Gnomad4 ASJ exome AF: 0.00459

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00314

Gnomad4 NFE exome AF: 0.00662

Gnomad4 OTH exome AF: 0.00380

GnomAD4 genome AF: 0.00397 AC: 605 AN: 152248 Hom.: 3 Cov.: 32 AF XY: 0.00344 AC XY: 256 AN XY: 74430

Gnomad4 AFR AF: 0.000891

Gnomad4 AMR AF: 0.000784

Gnomad4 ASJ AF: 0.00346

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00151

Gnomad4 NFE AF: 0.00763

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00630 Hom.: 1

Bravo AF: 0.00356

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 29, 2020	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

May 14, 2014

- -

Cornelia de Lange syndrome 4 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	11
DANN	Benign	0.76
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.2

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0012
dbscSNV1_RF	Benign	0.24
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

Publications

LitVar

Other links and lift over

dbSNP: rs200333487; hg19: chr8-117866718;