8-116847506-A-C

Variant names:

• chr8-116847506-A-C
• NM_006265.3:c.1890T>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_006265.3(RAD21):​c.1890T>G​(p.Ile630Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I630V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: RAD21 NM_006265.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0200
• 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_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.055222392).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAD21	NM_006265.3	c.1890T>G	p.Ile630Met	missense_variant	Exon 14 of 14	ENST00000297338.7	NP_006256.1
LOC112268030	XR_002956724.2	n.761-1382A>C		intron_variant	Intron 2 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAD21	ENST00000297338.7	c.1890T>G	p.Ile630Met	missense_variant	Exon 14 of 14	1	NM_006265.3	ENSP00000297338.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Cornelia de Lange syndrome 4 Uncertain:1

May 05, 2023

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.093	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	12
DANN	Benign	0.78
DEOGEN2	Benign	0.071	T;.;.;T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.34	N
LIST_S2	Benign	0.76	T;T;T;T
M_CAP	Benign	0.044	D
MetaRNN	Benign	0.055	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.90	L;.;.;.
PhyloP100		-0.020
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	0.47	N;N;N;N
REVEL	Benign	0.13
Sift	Uncertain	0.010	D;T;T;T
Sift4G	Benign	0.29	T;T;T;T
Polyphen		0.0010	B;.;.;.
Vest4		0.24
MutPred		0.23		Loss of sheet (P = 0.0357);.;.;.;
MVP		0.36
MPC		0.52
ClinPred		0.10	T
GERP RS		-9.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.16
gMVP		0.33
Mutation Taster		=81/19	polymorphism

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

hg19: chr8-117859745;