rs387907213

Variant names:

• chr8-116847643-A-G
• rs387907213
• NM_006265.3:c.1753T>C

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PS3 PM2 PP3_Moderate PP5

The NM_006265.3(RAD21):​c.1753T>C​(p.Cys585Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). ClinVar reports functional evidence for this variant: "SCV002243381: Experimental studies have shown that this missense change affects RAD21 function (PMID:22633399).".

• Frequency: Genomes: not found (cov: 33)
• Consequence: RAD21 NM_006265.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:1 O:1
• Conservation: PhyloP100: 9.31
• Publications: 13 publications found

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]

UTP23 (HGNC:28224): (UTP23 small subunit processome component) Enables mRNA 3'-UTR binding activity and mRNA 5'-UTR binding activity. Predicted to be involved in rRNA processing. Predicted to act upstream of or within endonucleolytic cleavage in 5'-ETS of tricistronic rRNA transcript (SSU-rRNA, 5.8S rRNA, LSU-rRNA). Predicted to be part of small-subunit processome. Predicted to be active in nucleolus. Implicated in colorectal adenocarcinoma. [provided by Alliance of Genome Resources, Apr 2022]

LOC112268030 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV002243381: Experimental studies have shown that this missense change affects RAD21 function (PMID: 22633399).
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.926
• PP5: Variant 8-116847643-A-G is Pathogenic according to our data. Variant chr8-116847643-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 35460.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006265.3. 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
	RAD21	NM_006265.3	MANE Select	c.1753T>C	p.Cys585Arg	missense	Exon 14 of 14	NP_006256.1	O60216

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAD21	ENST00000297338.7	TSL:1 MANE Select	c.1753T>C	p.Cys585Arg	missense	Exon 14 of 14	ENSP00000297338.2	O60216
	RAD21	ENST00000517749.2	TSL:1	c.1753T>C	p.Cys585Arg	missense	Exon 14 of 14	ENSP00000430273.2	O60216
	RAD21	ENST00000517485.6	TSL:3	c.1753T>C	p.Cys585Arg	missense	Exon 14 of 14	ENSP00000427923.2	O60216

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
3	-	-	Cornelia de Lange syndrome 4 (4)
1	1	-	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.73	D
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.74	T
M_CAP	Pathogenic	0.41	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Uncertain	0.18	D
MutationAssessor	Uncertain	2.7	M
PhyloP100		9.3
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-5.6	D
REVEL	Pathogenic	0.81
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.0080	D
Polyphen		0.99	D
Vest4		0.89
MutPred		0.75		Gain of disorder (P = 0.0076)
MVP		0.91
MPC		1.6
ClinPred		0.99	D
GERP RS		6.1
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.0
Varity_R		0.98
gMVP		0.78
Mutation Taster		=9/91	disease causing (ClinVar)

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: rs387907213; hg19: chr8-117859882;