chr8-116847549-G-A

Variant names:

• chr8-116847549-G-A
• rs2130449818
• NM_006265.3:c.1847C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1 PM2 PP3_Moderate PP5_Moderate

The NM_006265.3(RAD21):​c.1847C>T​(p.Pro616Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,728 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. P616P) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: RAD21 NM_006265.3 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.99
• Publications: 0 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 8 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_006265.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.93
• PP5: Variant 8-116847549-G-A is Pathogenic according to our data. Variant chr8-116847549-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 3429437.Status of the report is criteria_provided_single_submitter, 1 stars.

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.1847C>T	p.Pro616Leu	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.1847C>T	p.Pro616Leu	missense	Exon 14 of 14	ENSP00000297338.2	O60216
	RAD21	ENST00000517749.2	TSL:1	c.1847C>T	p.Pro616Leu	missense	Exon 14 of 14	ENSP00000430273.2	O60216
	RAD21	ENST00000517485.6	TSL:3	c.1847C>T	p.Pro616Leu	missense	Exon 14 of 14	ENSP00000427923.2	O60216

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461728 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727156

African (AFR) AF: 0.00 AC: 0 AN: 33470

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86240

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111912

Other (OTH) AF: 0.00 AC: 0 AN: 60388

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.78
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.39
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.72	D
Eigen	Pathogenic	0.96
Eigen_PC	Pathogenic	0.93
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Uncertain	0.28	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Uncertain	0.75	D
MutationAssessor	Uncertain	2.9	M
PhyloP100		10
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-6.8	D
REVEL	Pathogenic	0.77
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.80
MutPred		0.80		Loss of disorder (P = 0.038)
MVP		0.85
MPC		1.2
ClinPred		1.0	D
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.81
gMVP		0.76
Mutation Taster		=17/83	disease causing

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: rs2130449818; hg19: chr8-117859788;