NM_003579.4:c.767A>G

Variant names:

• chr1-46261261-A-G
• rs141167466
• NM_003579.4:c.767A>G

Variant summary

Our verdict is Uncertain significance. The variant received 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
• Publications: 0 publications found

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003579.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAD54L	NM_003579.4	MANE Select	c.767A>G	p.Glu256Gly	missense splice_region	Exon 8 of 18	NP_003570.2	Q92698
	RAD54L	NM_001142548.2		c.767A>G	p.Glu256Gly	missense splice_region	Exon 9 of 19	NP_001136020.1	Q92698
	RAD54L	NM_001370766.1		c.227A>G	p.Glu76Gly	missense splice_region	Exon 8 of 18	NP_001357695.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAD54L	ENST00000371975.9	TSL:1 MANE Select	c.767A>G	p.Glu256Gly	missense splice_region	Exon 8 of 18	ENSP00000361043.4	Q92698
	RAD54L	ENST00000932547.1		c.767A>G	p.Glu256Gly	missense splice_region	Exon 8 of 18	ENSP00000602606.1
	RAD54L	ENST00000442598.5	TSL:2	c.767A>G	p.Glu256Gly	missense splice_region	Exon 9 of 19	ENSP00000396113.1	Q92698

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
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
MetaSVM	Uncertain	-0.056	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		0.45
PrimateAI	Benign	0.34	T
PROVEAN	Uncertain	-2.9	D
REVEL	Uncertain	0.30
Sift	Benign	0.14	T
Sift4G	Benign	0.22	T
Polyphen		0.0030	B
Vest4		0.27
MutPred		0.47		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
Mutation Taster		=80/20	polymorphism

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

Other links and lift over

dbSNP: rs141167466; hg19: chr1-46726933;