rs28903094

Positions:

• chr5-132642304-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6 BP7 BS2

The NM_005732.4(RAD50):​c.3879C>T​(p.Ile1293=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0041 in 1,613,892 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0028 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0042 (16 hom.)
• Consequence: RAD50 NM_005732.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:12
• Conservation: PhyloP100: -1.48

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]

TH2LCRR (HGNC:40495): (T helper type 2 locus control region associated RNA)

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.6).
• BP6: Variant 5-132642304-C-T is Benign according to our data. Variant chr5-132642304-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 37384.We mark this variant Likely_benign, oryginal submissions are: {Benign=7, Likely_benign=3, Uncertain_significance=1}. Variant chr5-132642304-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-1.48 with no splicing effect.
• BS2: High Homozygotes in GnomAd4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RAD50	NM_005732.4	c.3879C>T	p.Ile1293=	synonymous_variant	25/25	ENST00000378823.8
TH2LCRR	NR_132125.1	n.105-22G>A		intron_variant, non_coding_transcript_variant
TH2LCRR	NR_132126.1	n.175-4039G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RAD50	ENST00000378823.8	c.3879C>T	p.Ile1293=	synonymous_variant	25/25	1	NM_005732.4	P1
TH2LCRR	ENST00000435042.1	n.95-22G>A		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.00276 AC: 419 AN: 152078 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00123

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00374

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000378

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00448

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.00249 AC: 626 AN: 251256 Hom.: 2 AF XY: 0.00242 AC XY: 328 AN XY: 135792

Gnomad AFR exome AF: 0.000861

Gnomad AMR exome AF: 0.00359

Gnomad ASJ exome AF: 0.000199

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000555

Gnomad NFE exome AF: 0.00400

Gnomad OTH exome AF: 0.00278

GnomAD4 exome AF: 0.00425 AC: 6206 AN: 1461696 Hom.: 16 Cov.: 31 AF XY: 0.00411 AC XY: 2989 AN XY: 727160

Gnomad4 AFR exome AF: 0.000986

Gnomad4 AMR exome AF: 0.00367

Gnomad4 ASJ exome AF: 0.000115

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.000524

Gnomad4 NFE exome AF: 0.00519

Gnomad4 OTH exome AF: 0.00339

GnomAD4 genome AF: 0.00275 AC: 419 AN: 152196 Hom.: 2 Cov.: 32 AF XY: 0.00266 AC XY: 198 AN XY: 74420

Gnomad4 AFR AF: 0.00123

Gnomad4 AMR AF: 0.00373

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000378

Gnomad4 NFE AF: 0.00448

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.00366 Hom.: 2

Bravo AF: 0.00309

EpiCase AF: 0.00371

EpiControl AF: 0.00350

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:12

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 25, 2013	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jan 05, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Apr 01, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 19, 2017	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

not provided Uncertain:1 Benign:3

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 16, 2017	Variant summary: The RAD50 c.3879C>T (p.Ile1293Ile) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a damaging outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. ESE finder predicts that this variant may affect multiple ESE sites. However, these predictions have yet to be confirmed by functional studies. This variant was found in 266/121258 control chromosomes (1 homozygote) at a frequency of 0.0021937, which is approximately 35 times the estimated maximal expected allele frequency of a pathogenic RAD50 variant (0.0000625), suggesting this variant is likely a benign polymorphism. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign/likely benign. Taken together, this variant is classified as benign. -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	RAD50: BP4, BP7, BS2 -

Hereditary cancer-predisposing syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 17, 2023	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. -

Nijmegen breakage syndrome-like disorder Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Counsyl	Aug 22, 2016	- -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	Oct 22, 2020	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.60
CADD	Benign	3.7
DANN	Benign	0.76

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: rs28903094; hg19: chr5-131977996; COSMIC: COSV104531510; COSMIC: COSV104531510;