1-46248514-G-T

Variant summary

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

The NM_003579.4(RAD54L):c.6G>T(p.Arg2Ser) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. R2T) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RAD54L NM_003579.4 missense, splice_region
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.36

Genes affected

RAD54L (HGNC:9826): (RAD54 like) The protein encoded by this gene belongs to the DEAD-like helicase superfamily, and shares similarity with Saccharomyces cerevisiae Rad54, a protein known to be involved in the homologous recombination and repair of DNA. This protein has been shown to play a role in homologous recombination related repair of DNA double-strand breaks. The binding of this protein to double-strand DNA induces a DNA topological change, which is thought to facilitate homologous DNA paring, and stimulate DNA recombination. Alternative splicing results in multiple transcript variants encoding the same protein.[provided by RefSeq, Dec 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	UniProt
RAD54L	NM_003579.4	c.6G>T	p.Arg2Ser	missense_variant, splice_region_variant	2/18	ENST00000371975.9
RAD54L	NM_001142548.2	c.6G>T	p.Arg2Ser	missense_variant, splice_region_variant	3/19
RAD54L	NM_001370766.1	c.-535G>T		splice_region_variant, 5_prime_UTR_variant	2/18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RAD54L	ENST00000371975.9	c.6G>T	p.Arg2Ser	missense_variant, splice_region_variant	2/18	1	NM_003579.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 15, 2022

The p.R2S variant (also known as c.6G>T), located in coding exon 2 of the RAD54L gene, results from a G to T substitution at nucleotide position 6. The arginine at codon 2 is replaced by serine, an amino acid with dissimilar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.78
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.070
Cadd	Pathogenic	27
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.42	T;T;T
Eigen	Benign	-0.12
Eigen_PC	Benign	-0.072
FATHMM_MKL	Benign	0.74	D
LIST_S2	Uncertain	0.93	D;.;.
M_CAP	Uncertain	0.15	D
MetaRNN	Uncertain	0.49	T;T;T
MetaSVM	Uncertain	-0.23	T
MutationAssessor	Uncertain	2.1	M;M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-2.3	N;N;.
REVEL	Uncertain	0.59
Sift	Uncertain	0.0040	D;D;.
Sift4G	Uncertain	0.0090	D;D;D
Polyphen		0.99	D;D;.
Vest4		0.61
MutPred		0.23		Gain of phosphorylation at R2 (P = 0.0045);Gain of phosphorylation at R2 (P = 0.0045);Gain of phosphorylation at R2 (P = 0.0045);
MVP		0.93
MPC		0.47
ClinPred		0.89	D
GERP RS		1.8
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.7
Varity_R		0.45
gMVP		0.65

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.32		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.32		Position offset: 3

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: chr1-46714186;