rs181016343

chr5-132609401-G-Achr5-132609401-G-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_005732.4(RAD50):c.3036+5G>A variant causes a splice donor 5th base, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000751 in 1,613,382 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00081 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00075 (5 hom.)
• Consequence: RAD50 NM_005732.4 splice_donor_5th_base, intron
• Scores: Splicing: ADA: 0.9774
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8 B:6
• Conservation: PhyloP100: 2.13

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BP6: Variant 5-132609401-G-A is Benign according to our data. Variant chr5-132609401-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 37381.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=8, Likely_benign=3, Benign=3}. Variant chr5-132609401-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.000745 (1089/1461162) while in subpopulation MID AF= 0.0153 (88/5762). AF 95% confidence interval is 0.0127. There are 5 homozygotes in gnomad4_exome. There are 544 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RAD50	NM_005732.4	c.3036+5G>A		splice_donor_5th_base_variant, intron_variant		ENST00000378823.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RAD50	ENST00000378823.8	c.3036+5G>A		splice_donor_5th_base_variant, intron_variant		1	NM_005732.4	P1
RAD50	ENST00000533482.5	c.*2662+5G>A		splice_donor_5th_base_variant, intron_variant, NMD_transcript_variant		1
RAD50	ENST00000651723.1	c.*3119+5G>A		splice_donor_5th_base_variant, intron_variant, NMD_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.000809 AC: 123 AN: 152102 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00144

Gnomad ASJ AF: 0.0158

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.000485

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00139 AC: 348 AN: 250832 Hom.: 0 AF XY: 0.00122 AC XY: 165 AN XY: 135596

Gnomad AFR exome AF: 0.0000617

Gnomad AMR exome AF: 0.00339

Gnomad ASJ exome AF: 0.0129

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.000164

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.000697

Gnomad OTH exome AF: 0.00180

GnomAD4 exome AF: 0.000745 AC: 1089 AN: 1461162 Hom.: 5 Cov.: 31 AF XY: 0.000748 AC XY: 544 AN XY: 726880

Gnomad4 AFR exome AF: 0.000179

Gnomad4 AMR exome AF: 0.00275

Gnomad4 ASJ exome AF: 0.0137

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.000371

Gnomad4 FIN exome AF: 0.0000750

Gnomad4 NFE exome AF: 0.000335

Gnomad4 OTH exome AF: 0.00171

GnomAD4 genome AF: 0.000808 AC: 123 AN: 152220 Hom.: 2 Cov.: 32 AF XY: 0.000672 AC XY: 50 AN XY: 74424

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00144

Gnomad4 ASJ AF: 0.0158

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000485

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00163 Hom.: 0

Bravo AF: 0.00101

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00136

EpiControl AF: 0.00107

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:8 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:2 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Vantari Genetics	Jan 06, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneKor MSA	Aug 01, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 04, 2021	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. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -

Nijmegen breakage syndrome-like disorder Uncertain:2 Benign:2

Uncertain significance, criteria provided, single submitter	curation	Department Of Genetics, Sultan Qaboos University Hospital, Sultan Qaboos University	Dec 30, 2017	- -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	Aug 10, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Sep 13, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

not specified Uncertain:2 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 20, 2017	Variant summary: The RAD50 c.3036+5G>A variant involves the alteration of a non-conserved intronic nucleotide. One in silico tool predicts a polymorphism outcome for this variant. 5/5 splice prediction tools predict a weakening effect on the canonical splicing donor site and 3/5 predict loss of a cryptic splicing donor site at the nucleotide of interest. However, these predictions have yet to be confirmed by functional studies. This variant was found in 352/276630 control chromosomes, predominantly observed in the Ashkenazi Jewish subpopulation at a frequency of 0.013132 (133/10128). This frequency is about 210 times the estimated maximal expected allele frequency of a pathogenic RAD50 variant (0.0000625), suggesting this is likely a benign polymorphism found primarily in the populations of Ashkenazi Jewish origin. This variant has been reported in affected individuals without strong evidence for causality. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely benign/VUS, all without evidence for independent evaluation. Taken together, this variant is currently classified as likely benign. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jun 24, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Mar 06, 2015	- -

not provided Uncertain:2 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Sep 26, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Sep 05, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Aug 10, 2017	RAD50 has been only recently described in association with cancer predisposition and the risks are not well understood. This variant is denoted RAD50 IVS19+5G>A, or c.3036+5G>A and consists of a G>A nucleotide substitution at the +5 position of intron 19 of the RAD50 gene. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. RAD50 3036+5G>A occurs at a position that is well conserved throughout evolution. This particular nucleotide substitution was observed in multiple subpopulations, with the highest allele frequency of 0.09% (8/8588) in European Americans in the NHLBI Exome Sequencing Project. Multiple in silico splicing models predict a reduced likelihood that the nearby canonical donor splice site is utilized. At the molecular level, the impact of this missense variant on protein structure and function is not known and we consider this to be a variant of uncertain significance. Futhermore, based on the currently available information, cancer risks associated with this variant, and the RAD50 gene, remain unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
Cadd	Uncertain	24
Dann	Benign	0.88
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.98
dbscSNV1_RF	Benign	0.67
SpliceAI score (max)		0.020		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: rs181016343; hg19: chr5-131945093;