1-46261261-A-G

Position:

• chr1-46261261-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_003579.4(RAD54L):​c.767A>G​(p.Glu256Gly) 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. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. 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. E256V) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: RAD54L NM_003579.4 missense, splice_region
• Scores: Splicing: ADA: 0.02384
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.448

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]

LRRC41 (HGNC:16917): (leucine rich repeat containing 41) Predicted to enable identical protein binding activity. Predicted to be involved in protein ubiquitination. Located in membrane. [provided by Alliance of Genome Resources, Apr 2022]

RAD54L (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.31238487).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RAD54L	NM_003579.4	c.767A>G	p.Glu256Gly	missense_variant, splice_region_variant	8/18	ENST00000371975.9	NP_003570.2
RAD54L	NM_001142548.2	c.767A>G	p.Glu256Gly	missense_variant, splice_region_variant	9/19		NP_001136020.1
RAD54L	NM_001370766.1	c.227A>G	p.Glu76Gly	missense_variant, splice_region_variant	8/18		NP_001357695.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RAD54L	ENST00000371975.9	c.767A>G	p.Glu256Gly	missense_variant, splice_region_variant	8/18	1	NM_003579.4	ENSP00000361043.4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 31

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

Mar 31, 2023

The p.E256G variant (also known as c.767A>G) is located in coding exon 8 of the RAD54L gene. The glutamic acid at codon 256 is replaced by glycine, an amino acid with similar properties. This change occurs in the first base pair of coding exon 8. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. 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	Benign	0.090
BayesDel_addAF	Uncertain	0.025	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.74	D;D
Eigen	Benign	-0.050
Eigen_PC	Benign	0.092
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.81	T;.
M_CAP	Uncertain	0.096	D
MetaRNN	Benign	0.31	T;T
MetaSVM	Uncertain	-0.056	T
MutationAssessor	Uncertain	2.0	M;M
PrimateAI	Benign	0.34	T
PROVEAN	Uncertain	-2.9	D;D
REVEL	Uncertain	0.30
Sift	Benign	0.14	T;T
Sift4G	Benign	0.22	T;T
Polyphen		0.0030	B;B
Vest4		0.27
MutPred		0.47		Loss of helix (P = 0.0626);Loss of helix (P = 0.0626);
MVP		0.96
MPC		0.15
ClinPred		0.57	D
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.12
gMVP		0.48

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.024
dbscSNV1_RF	Benign	0.31
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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-46726933;