1-46261278-C-A

Variant names:

• chr1-46261278-C-A
• rs775691979
• NM_003579.4:c.784C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003579.4(RAD54L):​c.784C>A​(p.Arg262Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,668 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R262H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: RAD54L NM_003579.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.90
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.18155533).

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.784C>A	p.Arg262Ser	missense	Exon 8 of 18	NP_003570.2	Q92698
	RAD54L	NM_001142548.2		c.784C>A	p.Arg262Ser	missense	Exon 9 of 19	NP_001136020.1	Q92698
	RAD54L	NM_001370766.1		c.244C>A	p.Arg82Ser	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.784C>A	p.Arg262Ser	missense	Exon 8 of 18	ENSP00000361043.4	Q92698
	RAD54L	ENST00000932547.1		c.784C>A	p.Arg262Ser	missense	Exon 8 of 18	ENSP00000602606.1
	RAD54L	ENST00000442598.5	TSL:2	c.784C>A	p.Arg262Ser	missense	Exon 9 of 19	ENSP00000396113.1	Q92698

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461668 Hom.: 0 Cov.: 36 AF XY: 0.00000138 AC XY: 1 AN XY: 727154

African (AFR) AF: 0.0000299 AC: 1 AN: 33432

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.00 AC: 0 AN: 86238

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53398

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111948

Other (OTH) AF: 0.00 AC: 0 AN: 60356

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Uncertain	0.082	D
BayesDel_noAF	Benign	-0.12
CADD	Benign	22
DANN	Benign	0.83
DEOGEN2	Benign	0.34	T
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.074
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.18	T
MetaSVM	Uncertain	-0.27	T
MutationAssessor	Benign	-0.62	N
PhyloP100		3.9
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.13	N
REVEL	Uncertain	0.34
Sift	Benign	1.0	T
Sift4G	Uncertain	0.018	D
Polyphen		0.020	B
Vest4		0.58
MutPred		0.43		Gain of disorder (P = 0.0514)
MVP		0.92
MPC		0.15
ClinPred		0.64	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.15
gMVP		0.53
Mutation Taster		=86/14	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs775691979; hg19: chr1-46726950;