chr8-116847588-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM2PP2PP3_StrongPP5_Moderate

The NM_006265.3(RAD21):ā€‹c.1808T>Cā€‹(p.Leu603Pro) 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. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (ā˜…).

Frequency

Genomes: not found (cov: 32)
Exomes š‘“: 0.0 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

RAD21
NM_006265.3 missense

Scores

15
3
1

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 9.31
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), RAD21. . Gene score misZ 2.6421 (greater than the threshold 3.09). Trascript score misZ 3.6451 (greater than threshold 3.09). GenCC has associacion of gene with Cornelia de Lange syndrome, Cornelia de Lange syndrome 4, Mungan syndrome.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.989
PP5
Variant 8-116847588-A-G is Pathogenic according to our data. Variant chr8-116847588-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 216988.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
RAD21NM_006265.3 linkuse as main transcriptc.1808T>C p.Leu603Pro missense_variant 14/14 ENST00000297338.7
LOC112268030XR_002956724.2 linkuse as main transcriptn.761-1300A>G intron_variant, non_coding_transcript_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
RAD21ENST00000297338.7 linkuse as main transcriptc.1808T>C p.Leu603Pro missense_variant 14/141 NM_006265.3 P1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
0.00
AC:
0
AN:
1461810
Hom.:
0
Cov.:
30
AF XY:
0.00
AC XY:
0
AN XY:
727206
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Cornelia de Lange syndrome 4 Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingUCLA Clinical Genomics Center, UCLAOct 16, 2012- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.59
D
BayesDel_noAF
Pathogenic
0.60
CADD
Pathogenic
29
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.77
D;.;.;D
Eigen
Pathogenic
1.0
Eigen_PC
Pathogenic
0.96
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.96
D;D;D;D
M_CAP
Pathogenic
0.69
D
MetaRNN
Pathogenic
0.99
D;D;D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
3.4
M;.;.;.
MutationTaster
Benign
1.0
D;D;D;D;D;D
PrimateAI
Pathogenic
0.94
D
PROVEAN
Pathogenic
-6.2
D;D;D;D
REVEL
Pathogenic
0.98
Sift
Pathogenic
0.0
D;D;D;D
Sift4G
Pathogenic
0.0
D;D;D;D
Polyphen
1.0
D;.;.;.
Vest4
0.99
MutPred
0.92
Gain of glycosylation at L603 (P = 0.0465);.;.;.;
MVP
0.98
MPC
1.5
ClinPred
1.0
D
GERP RS
6.1
Varity_R
0.99
gMVP
0.92

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs863224910; hg19: chr8-117859827; API