NM_005732.4:c.551+19G>A

Variant names:

• chr5-132579521-G-A
• rs17166050
• NM_005732.4:c.551+19G>A

Variant summary

Our verdict is Benign. The variant received -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:9
• Conservation: PhyloP100: -0.192
• Publications: 29 publications found

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]

RAD50 Gene-Disease associations (from GenCC):

• Nijmegen breakage syndrome-like disorder

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• familial ovarian cancer

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
• hereditary breast carcinoma

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ENSG00000283782 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 259870.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.214 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005732.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAD50	NM_005732.4	MANE Select	c.551+19G>A		intron	N/A	NP_005723.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAD50	ENST00000378823.8	TSL:1 MANE Select	c.551+19G>A		intron	N/A	ENSP00000368100.4
	ENSG00000283782	ENST00000638452.2	TSL:5	c.254+19G>A		intron	N/A	ENSP00000492349.2
	RAD50	ENST00000416135.5	TSL:1	c.254+19G>A		intron	N/A	ENSP00000389515.1

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

GnomAD2 exomes AF: 0.197 AC: 49412 AN: 250610 AF XY: 0.202

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 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

African (AFR) AF: 0.108 AC: 3558 AN: 33078

American (AMR) AF: 0.146 AC: 6532 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.233 AC: 6064 AN: 26044

East Asian (EAS) AF: 0.192 AC: 7606 AN: 39572

South Asian (SAS) AF: 0.226 AC: 19386 AN: 85672

European-Finnish (FIN) AF: 0.253 AC: 13506 AN: 53316

Middle Eastern (MID) AF: 0.203 AC: 963 AN: 4746

European-Non Finnish (NFE) AF: 0.196 AC: 215150 AN: 1098462

Other (OTH) AF: 0.188 AC: 11273 AN: 59812

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

African (AFR) AF: 0.116 AC: 4798 AN: 41510

American (AMR) AF: 0.146 AC: 2226 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.233 AC: 808 AN: 3468

East Asian (EAS) AF: 0.176 AC: 914 AN: 5182

South Asian (SAS) AF: 0.225 AC: 1085 AN: 4824

European-Finnish (FIN) AF: 0.245 AC: 2582 AN: 10556

Middle Eastern (MID) AF: 0.204 AC: 60 AN: 294

European-Non Finnish (NFE) AF: 0.215 AC: 14589 AN: 67962

Other (OTH) AF: 0.183 AC: 386 AN: 2108

Alfa AF: 0.208 Hom.: 1262

Bravo AF: 0.168

Asia WGS AF: 0.188 AC: 656 AN: 3476

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Nijmegen breakage syndrome-like disorder (3)
-	-	2	Hereditary cancer-predisposing syndrome (2)
-	-	2	not provided (2)
-	-	1	Familial cancer of breast (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.0
DANN	Benign	0.41
PhyloP100		-0.19
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs17166050; hg19: chr5-131915213; COSMIC: COSV99528535;