3-51629381-A-G

Variant names:

• chr3-51629381-A-G
• NM_015106.4:c.389A>G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3 PP5

The NM_015106.4(RAD54L2):​c.389A>G​(p.Gln130Arg) 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 Likely pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: RAD54L2 NM_015106.4 missense
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 8.95

Genes affected

RAD54L2 (HGNC:29123): (RAD54 like 2) Predicted to enable ATP hydrolysis activity; protein kinase binding activity; and transcription coregulator activity. Predicted to be involved in DNA duplex unwinding. Predicted to act upstream of or within positive regulation of transcription by RNA polymerase II. Predicted to be located in nuclear speck. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.749
• PP5: Variant 3-51629381-A-G is Pathogenic according to our data. Variant chr3-51629381-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3374700.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAD54L2	NM_015106.4	c.389A>G	p.Gln130Arg	missense_variant	Exon 5 of 23	ENST00000684192.1	NP_055921.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAD54L2	ENST00000684192.1	c.389A>G	p.Gln130Arg	missense_variant	Exon 5 of 23		NM_015106.4	ENSP00000507587.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

TOP2 deficiency type 1 Pathogenic:1

-

University Medical Center Utrecht, University Utrecht

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing;in vitro

De novo variant in RAD54L2 that is absent in father/mother of the individual (trio Whole Exome Sequencing). Predicted as disease-causing by multiple lines of computational evidence. MutationTaster: disease causing (probability 0.99). Cadd score: 25.7. Low tolerance against loss-of-function (pLI=1). Highly conserved region of the protein, including Gln130 (Phastcons=1, PhyloP=4.58). Structural information about the variant/impact of the variant cannot be provided as the crystal structure of the N-terminal region of RAD4L2 is not known. We studied DNA damage repair capacity after X-ray irradiation and/or after etoposide treatment, a chemotherapeutic agent that stabilizes DNA topoisomerase II cleavage complexes (TOP2ccs), as RAD54L2 is involved in TOP2cc resolution. (D'Alessandro et al., 2023). RAD54L2 knockout cell lines show increased sensitivity to Etoposide treatment.(D'Alessandro et al., 2023). While survival after X-ray irradiation was not appreciably affected in patient-derived fibroblasts of the individual with RAD54L2 VUS, we observed decreased survival of fibroblasts upon etoposide treatment compared to healthy control cells. In addition, compared to control cells, we observed increased yH2AX foci in patient-derived fibroblasts of the indiviudal with RAD54L2 VUS immediately after etoposide treatment (0 hour), which normalized after 4 and 8 hours. Additionally, we did not observe any changes in yH2AX foci levels in individual 106 upon treatment with ionizing radiations, in agreement to the survival data. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.72
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.53	D
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.018	T
MetaRNN	Pathogenic	0.75	D
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.6	M
PrimateAI	Pathogenic	0.80	T
PROVEAN	Uncertain	-3.4	D
REVEL	Uncertain	0.34
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.010	D
Polyphen		0.98	D
Vest4		0.74
MutPred		0.31		Gain of MoRF binding (P = 0.0199);
MVP		0.55
MPC		1.5
ClinPred		0.99	D
GERP RS		5.7
Varity_R		0.41
gMVP		0.47

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-51663397;