NM_003579.4:c.796G>C

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_Moderate BP6

The NM_003579.4(RAD54L):​c.796G>C​(p.Val266Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000103 in 1,613,732 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V266M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000086 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00010 (0 hom.)
• Consequence: RAD54L NM_003579.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 4.96
• Publications: 1 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: Likely_benign. The variant received -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.20010442).
• BP6: Variant 1-46261290-G-C is Benign according to our data. Variant chr1-46261290-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 801487.

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>C	p.Val266Leu	missense	Exon 8 of 18	NP_003570.2	Q92698
	RAD54L	NM_001142548.2		c.796G>C	p.Val266Leu	missense	Exon 9 of 19	NP_001136020.1	Q92698
	RAD54L	NM_001370766.1		c.256G>C	p.Val86Leu	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>C	p.Val266Leu	missense	Exon 8 of 18	ENSP00000361043.4	Q92698
	RAD54L	ENST00000932547.1		c.796G>C	p.Val266Leu	missense	Exon 8 of 18	ENSP00000602606.1
	RAD54L	ENST00000442598.5	TSL:2	c.796G>C	p.Val266Leu	missense	Exon 9 of 19	ENSP00000396113.1	Q92698

Frequencies

GnomAD3 genomes AF: 0.0000856 AC: 13 AN: 151804 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000485

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000517 AC: 13 AN: 251464 AF XY: 0.0000441

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000106

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000105 AC: 153 AN: 1461810 Hom.: 0 Cov.: 36 AF XY: 0.000117 AC XY: 85 AN XY: 727204

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53402

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000134 AC: 149 AN: 1111952

Other (OTH) AF: 0.0000662 AC: 4 AN: 60394

GnomAD4 genome AF: 0.0000856 AC: 13 AN: 151922 Hom.: 0 Cov.: 31 AF XY: 0.0000673 AC XY: 5 AN XY: 74254

African (AFR) AF: 0.0000483 AC: 2 AN: 41384

American (AMR) AF: 0.000131 AC: 2 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5162

South Asian (SAS) AF: 0.00 AC: 0 AN: 4786

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10546

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 67990

Other (OTH) AF: 0.00 AC: 0 AN: 2104

Alfa AF: 0.000149 Hom.: 1

Bravo AF: 0.000117

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000412 AC: 5

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	Non-Hodgkin lymphoma (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.046	T
BayesDel_noAF	Benign	-0.10
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.50	T
Eigen	Benign	-0.17
Eigen_PC	Benign	0.061
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.036	D
MetaRNN	Benign	0.20	T
MetaSVM	Uncertain	-0.24	T
MutationAssessor	Benign	0.39	N
PhyloP100		5.0
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-1.2	N
REVEL	Uncertain	0.43
Sift	Benign	0.27	T
Sift4G	Pathogenic	0.0	D
Polyphen		0.0040	B
Vest4		0.49
MutPred		0.43		Loss of helix (P = 0.1706)
MVP		0.94
MPC		0.13
ClinPred		0.076	T
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.092
gMVP		0.60
Mutation Taster		=93/7	polymorphism

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

Other links and lift over

dbSNP: rs139487723; hg19: chr1-46726962;