rs775145190

Positions:

• chr5-132588069-C-T

Variant summary

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

The NM_005732.4(RAD50):​c.1031C>T​(p.Ser344Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,460,286 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 Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. S344S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: RAD50 NM_005732.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 3.82

Genes affected

RAD50 (HGNC:9816): (RAD50 double strand break repair protein) The protein encoded by this gene is highly similar to Saccharomyces cerevisiae Rad50, a protein involved in DNA double-strand break repair. This protein forms a complex with MRE11 and NBS1. The protein complex binds to DNA and displays numerous enzymatic activities that are required for nonhomologous joining of DNA ends. This protein, cooperating with its partners, is important for DNA double-strand break repair, cell cycle checkpoint activation, telomere maintenance, and meiotic recombination. Knockout studies of the mouse homolog suggest this gene is essential for cell growth and viability. Mutations in this gene are the cause of Nijmegen breakage syndrome-like disorder.[provided by RefSeq, Apr 2010]

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=0.20217258).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RAD50	NM_005732.4	c.1031C>T	p.Ser344Leu	missense_variant	7/25	ENST00000378823.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RAD50	ENST00000378823.8	c.1031C>T	p.Ser344Leu	missense_variant	7/25	1	NM_005732.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000799 AC: 2 AN: 250418 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135378

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000886

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1460286 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726514

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000113

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Dec 26, 2022	In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt RAD50 protein function. ClinVar contains an entry for this variant (Variation ID: 231358). This variant has not been reported in the literature in individuals affected with RAD50-related conditions. This variant is present in population databases (rs775145190, gnomAD 0.006%). This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 344 of the RAD50 protein (p.Ser344Leu). -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 12, 2023	The p.S344L variant (also known as c.1031C>T), located in coding exon 7 of the RAD50 gene, results from a C to T substitution at nucleotide position 1031. The serine at codon 344 is replaced by leucine, an amino acid with dissimilar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be benign and tolerated by PolyPhen and SIFT in silico analyses, respectively. 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	Benign	0.28
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.34	.;.;.;T;T
Eigen	Benign	0.072
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.97	.;.;D;D;D
M_CAP	Benign	0.0055	T
MetaRNN	Benign	0.20	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	.;.;.;L;.
MutationTaster	Benign	0.63	D;D
PrimateAI	Uncertain	0.51	T
PROVEAN	Uncertain	-2.7	.;.;.;.;D
REVEL	Benign	0.059
Sift	Uncertain	0.023	.;.;.;.;D
Sift4G	Benign	0.078	.;.;.;T;T
Polyphen		0.0020	.;.;.;B;.
Vest4		0.42
MutPred		0.30		.;.;.;Loss of phosphorylation at S344 (P = 0.0287);Loss of phosphorylation at S344 (P = 0.0287);
MVP		0.51
ClinPred		0.86	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.10
gMVP		0.30

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs775145190; hg19: chr5-131923761;