1-46261290-G-A

Variant names:

• chr1-46261290-G-A
• rs139487723
• NM_003579.4:c.796G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_003579.4(RAD54L):​c.796G>A​(p.Val266Met) variant causes a missense change. 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. V266L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: RAD54L NM_003579.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.96
• 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 2 ACMG points.

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

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.796G>A	p.Val266Met	missense	Exon 8 of 18	NP_003570.2	Q92698
	RAD54L	NM_001142548.2		c.796G>A	p.Val266Met	missense	Exon 9 of 19	NP_001136020.1	Q92698
	RAD54L	NM_001370766.1		c.256G>A	p.Val86Met	missense	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.796G>A	p.Val266Met	missense	Exon 8 of 18	ENSP00000361043.4	Q92698
	RAD54L	ENST00000932547.1		c.796G>A	p.Val266Met	missense	Exon 8 of 18	ENSP00000602606.1
	RAD54L	ENST00000442598.5	TSL:2	c.796G>A	p.Val266Met	missense	Exon 9 of 19	ENSP00000396113.1	Q92698

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions as Germline

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	0.22
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.53	D
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.031	D
MetaRNN	Uncertain	0.51	D
MetaSVM	Uncertain	0.62	D
MutationAssessor	Benign	2.0	M
PhyloP100		5.0
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-1.3	N
REVEL	Uncertain	0.52
Sift	Uncertain	0.0090	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.91	P
Vest4		0.55
MutPred		0.43		Gain of disorder (P = 0.055)
MVP		0.97
MPC		0.21
ClinPred		0.63	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Varity_R		0.098
gMVP		0.58
Mutation Taster		=92/8	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs139487723; hg19: chr1-46726962; COSMIC: COSV64336712; COSMIC: COSV64336712;