rs17166050

chr5-132579521-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005732.4(RAD50):c.551+19G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.195 in 1,597,502 control chromosomes in the GnomAD database, including 31,613 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.18 (2701 hom., cov: 32)
  • Exomes 𝑓: 0.20 (28912 hom.)
• Consequence: RAD50 NM_005732.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.192

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 5-132579521-G-A is Benign according to our data. Variant chr5-132579521-G-A is described in ClinVar as [Benign]. Clinvar id is 259870.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-132579521-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.214 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RAD50	NM_005732.4	c.551+19G>A		intron_variant		ENST00000378823.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RAD50	ENST00000378823.8	c.551+19G>A		intron_variant		1	NM_005732.4	P1

Frequencies

GnomAD3 genomes AF: 0.181 AC: 27552 AN: 151980 Hom.: 2697 Cov.: 32

Gnomad AFR AF: 0.116

Gnomad AMI AF: 0.122

Gnomad AMR AF: 0.146

Gnomad ASJ AF: 0.233

Gnomad EAS AF: 0.176

Gnomad SAS AF: 0.225

Gnomad FIN AF: 0.245

Gnomad MID AF: 0.203

Gnomad NFE AF: 0.215

Gnomad OTH AF: 0.185

GnomAD3 exomes AF: 0.197 AC: 49412 AN: 250610 Hom.: 5184 AF XY: 0.202 AC XY: 27455 AN XY: 135612

Gnomad AFR exome AF: 0.113

Gnomad AMR exome AF: 0.144

Gnomad ASJ exome AF: 0.229

Gnomad EAS exome AF: 0.168

Gnomad SAS exome AF: 0.228

Gnomad FIN exome AF: 0.255

Gnomad NFE exome AF: 0.208

Gnomad OTH exome AF: 0.200

GnomAD4 exome AF: 0.197 AC: 284038 AN: 1445404 Hom.: 28912 Cov.: 31 AF XY: 0.199 AC XY: 143156 AN XY: 719884

Gnomad4 AFR exome AF: 0.108

Gnomad4 AMR exome AF: 0.146

Gnomad4 ASJ exome AF: 0.233

Gnomad4 EAS exome AF: 0.192

Gnomad4 SAS exome AF: 0.226

Gnomad4 FIN exome AF: 0.253

Gnomad4 NFE exome AF: 0.196

Gnomad4 OTH exome AF: 0.188

GnomAD4 genome AF: 0.181 AC: 27559 AN: 152098 Hom.: 2701 Cov.: 32 AF XY: 0.183 AC XY: 13623 AN XY: 74350

Gnomad4 AFR AF: 0.116

Gnomad4 AMR AF: 0.146

Gnomad4 ASJ AF: 0.233

Gnomad4 EAS AF: 0.176

Gnomad4 SAS AF: 0.225

Gnomad4 FIN AF: 0.245

Gnomad4 NFE AF: 0.215

Gnomad4 OTH AF: 0.183

Alfa AF: 0.210 Hom.: 779

Bravo AF: 0.168

Asia WGS AF: 0.188 AC: 656 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 24, 2016	Variant summary: The RAD50 c.551+19G>A variant involves the alteration of a non-conserved intronic nucleotide. One in silico tool predicts a benign outcome for this variant along with 4/5 splice site tools predicting the variant not to have an impact on splicing. This variant was found in 24021/120846 control chromosomes (2524 homozygotes) at a frequency of 0.1987736, which greatly exceeds the estimated maximal expected allele frequency of a pathogenic RAD50 variant (0.0000625), suggesting this variant is a common benign polymorphism. Taken together, this variant is classified as Benign. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 24093751) -

Nijmegen breakage syndrome-like disorder Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Jul 28, 2017	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Familial cancer of breast Benign:1

Benign, criteria provided, single submitter

clinical testing

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Jul 07, 2023

- -

Hereditary cancer-predisposing syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
Cadd	Benign	1.0
Dann	Benign	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: rs17166050; hg19: chr5-131915213; COSMIC: COSV99528535; COSMIC: COSV99528535;