1-46261279-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003579.4(RAD54L):c.785G>A(p.Arg262His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000992 in 1,612,890 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. 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. R262C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: RAD54L NM_003579.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.81

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

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14223915).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RAD54L	NM_003579.4	c.785G>A	p.Arg262His	missense_variant	8/18	ENST00000371975.9
RAD54L	NM_001142548.2	c.785G>A	p.Arg262His	missense_variant	9/19
RAD54L	NM_001370766.1	c.245G>A	p.Arg82His	missense_variant	8/18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RAD54L	ENST00000371975.9	c.785G>A	p.Arg262His	missense_variant	8/18	1	NM_003579.4	P1

Frequencies

GnomAD3 genomes AF: 0.00000661 AC: 1 AN: 151216 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000659

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: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000199 AC: 5 AN: 251464 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135908

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000217

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000103 AC: 15 AN: 1461674 Hom.: 0 Cov.: 36 AF XY: 0.0000110 AC XY: 8 AN XY: 727160

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000176

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000661 AC: 1 AN: 151216 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 73768

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000659

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ExAC AF: 0.00000824 AC: 1

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

Oct 03, 2023

The c.785G>A (p.R262H) alteration is located in exon 8 (coding exon 8) of the RAD54L gene. This alteration results from a G to A substitution at nucleotide position 785, causing the arginine (R) at amino acid position 262 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.22
Cadd	Benign	19
Dann	Benign	0.93
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.37
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.83	T;T;.
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.14	T;T;T
MetaSVM	Benign	-0.36	T
MutationTaster	Benign	0.97	D;D
PrimateAI	Benign	0.37	T
Sift4G	Uncertain	0.016	D;T;T
Polyphen		0.0040	.;B;B
Vest4		0.22
MutPred		0.47		.;Gain of disorder (P = 0.1587);Gain of disorder (P = 0.1587);
MVP		0.88
MPC		0.16
ClinPred		0.063	T
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.020
gMVP		0.41

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

Publications

LitVar

Other links and lift over

dbSNP: rs141226335; hg19: chr1-46726951; COSMIC: COSV64336296; COSMIC: COSV64336296;