rs786201357

Positions:

• chr5-132589640-G-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP6

The NM_005732.4(RAD50):​c.1255G>A​(p.Ala419Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000021 in 1,431,316 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: RAD50 NM_005732.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 0.180

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]

ENSG00000283782 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.037546188).
• BP6: Variant 5-132589640-G-A is Benign according to our data. Variant chr5-132589640-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 184246.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RAD50	NM_005732.4	c.1255G>A	p.Ala419Thr	missense_variant	9/25	ENST00000378823.8	NP_005723.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RAD50	ENST00000378823.8	c.1255G>A	p.Ala419Thr	missense_variant	9/25	1	NM_005732.4	ENSP00000368100.4
ENSG00000283782	ENST00000640655.2	c.958G>A	p.Ala320Thr	missense_variant	10/26	5		ENSP00000491596.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000425 AC: 1 AN: 235552 Hom.: 0 AF XY: 0.00000783 AC XY: 1 AN XY: 127660

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000322

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000210 AC: 3 AN: 1431316 Hom.: 0 Cov.: 30 AF XY: 0.00000281 AC XY: 2 AN XY: 711608

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000246

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000508

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jun 23, 2023	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 419 of the RAD50 protein (p.Ala419Thr). 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: 184246). This variant has not been reported in the literature in individuals affected with RAD50-related conditions. This variant is present in population databases (rs786201357, gnomAD 0.003%). -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 28, 2024	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Quest Diagnostics Nichols Institute San Juan Capistrano

Aug 03, 2023

This variant has not been reported in individuals with RAD50-related conditions in the published literature. The frequency of this variant in the general population, 0.0000042 (1/235552 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant. -

Nijmegen breakage syndrome-like disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 15, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	15
DANN	Benign	0.92
DEOGEN2	Benign	0.072	.;.;.;T;T
Eigen	Benign	-0.69
Eigen_PC	Benign	-0.49
FATHMM_MKL	Benign	0.75	D
LIST_S2	Benign	0.65	.;.;T;T;T
M_CAP	Benign	0.0086	T
MetaRNN	Benign	0.038	T;T;T;T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	-0.60	.;.;.;N;.
PrimateAI	Benign	0.25	T
PROVEAN	Benign	0.050	.;.;.;.;N
REVEL	Benign	0.061
Sift	Benign	0.64	.;.;.;.;T
Sift4G	Benign	0.56	.;.;.;T;T
Polyphen		0.0	.;.;.;B;.
Vest4		0.094
MutPred		0.23		.;.;.;Gain of phosphorylation at A419 (P = 0.0339);Gain of phosphorylation at A419 (P = 0.0339);
MVP		0.33
ClinPred		0.059	T
GERP RS		0.051
Varity_R		0.022
gMVP		0.16

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs786201357; hg19: chr5-131925332;