rs1554611589

Positions:

• chr8-116858415-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_006265.3(RAD21):​c.418G>A​(p.Val140Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: RAD21 NM_006265.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 7.57

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RAD21	NM_006265.3	c.418G>A	p.Val140Met	missense_variant	5/14	ENST00000297338.7	NP_006256.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RAD21	ENST00000297338.7	c.418G>A	p.Val140Met	missense_variant	5/14	1	NM_006265.3	ENSP00000297338.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 01, 2014

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jul 19, 2023

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.68
BayesDel_addAF	Uncertain	0.024	T
BayesDel_noAF	Benign	-0.20
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.25	T;T;T
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D;D
M_CAP	Benign	0.029	D
MetaRNN	Uncertain	0.43	T;T;T
MetaSVM	Benign	-0.45	T
MutationAssessor	Uncertain	2.4	M;.;.
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-1.6	N;N;N
REVEL	Benign	0.20
Sift	Uncertain	0.015	D;T;T
Sift4G	Uncertain	0.049	D;T;.
Polyphen		1.0	D;.;.
Vest4		0.53
MutPred		0.24		Gain of disorder (P = 0.0559);Gain of disorder (P = 0.0559);Gain of disorder (P = 0.0559);
MVP		0.50
MPC		2.0
ClinPred		0.93	D
GERP RS		5.7
Varity_R		0.25
gMVP		0.58

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

Other links and lift over

dbSNP: rs1554611589; hg19: chr8-117870654;