1-46248530-A-C

Position:

• chr1-46248530-A-C

Variant summary

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

The NM_003579.4(RAD54L):​c.22A>C​(p.Ser8Arg) 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 nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RAD54L NM_003579.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.89

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]

RAD54L (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RAD54L	NM_003579.4	c.22A>C	p.Ser8Arg	missense_variant	2/18	ENST00000371975.9	NP_003570.2
RAD54L	NM_001142548.2	c.22A>C	p.Ser8Arg	missense_variant	3/19		NP_001136020.1
RAD54L	NM_001370766.1	c.-519A>C		5_prime_UTR_variant	2/18		NP_001357695.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RAD54L	ENST00000371975.9	c.22A>C	p.Ser8Arg	missense_variant	2/18	1	NM_003579.4	ENSP00000361043.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

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

May 24, 2022

The p.S8R variant (also known as c.22A>C), located in coding exon 2 of the RAD54L gene, results from an A to C substitution at nucleotide position 22. The serine at codon 8 is replaced by arginine, an amino acid with dissimilar properties. This amino acid position is conserved. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.32
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.45	T;T;T
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.94	D;.;.
M_CAP	Uncertain	0.14	D
MetaRNN	Uncertain	0.45	T;T;T
MetaSVM	Uncertain	0.46	D
MutationAssessor	Uncertain	2.1	M;M;.
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-2.4	N;N;.
REVEL	Uncertain	0.49
Sift	Pathogenic	0.0	D;D;.
Sift4G	Benign	0.10	T;T;T
Polyphen		1.0	D;D;.
Vest4		0.74
MutPred		0.19		Loss of phosphorylation at S8 (P = 0.0069);Loss of phosphorylation at S8 (P = 0.0069);Loss of phosphorylation at S8 (P = 0.0069);
MVP		0.97
MPC		0.62
ClinPred		0.98	D
GERP RS		5.7
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		2.7
Varity_R		0.77
gMVP		0.68

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-46714202;