rs1804670

Variant names:

• chr5-132642271-T-C
• rs1804670
• NM_005732.4:c.3846T>C

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_005732.4(RAD50):​c.3846T>C​(p.Tyr1282Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00948 in 1,613,976 control chromosomes in the GnomAD database, including 1,128 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.048 (569 hom., cov: 32)
  • Exomes 𝑓: 0.0055 (559 hom.)
• Consequence: RAD50 NM_005732.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.0570

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:):

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

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.35).
• BP6: Variant 5-132642271-T-C is Benign according to our data. Variant chr5-132642271-T-C is described in ClinVar as [Benign]. Clinvar id is 183705.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.057 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.163 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAD50	NM_005732.4	c.3846T>C	p.Tyr1282Tyr	synonymous_variant	Exon 25 of 25	ENST00000378823.8	NP_005723.2
TH2LCRR	NR_132125.1	n.116A>G		non_coding_transcript_exon_variant	Exon 2 of 3
TH2LCRR	NR_132126.1	n.175-4006A>G		intron_variant	Intron 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAD50	ENST00000378823.8	c.3846T>C	p.Tyr1282Tyr	synonymous_variant	Exon 25 of 25	1	NM_005732.4	ENSP00000368100.4
ENSG00000283782	ENST00000640655.2	c.3549T>C	p.Tyr1183Tyr	synonymous_variant	Exon 26 of 26	5		ENSP00000491596.2

Frequencies

GnomAD3 genomes AF: 0.0477 AC: 7251 AN: 152162 Hom.: 569 Cov.: 32

Gnomad AFR AF: 0.166

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0157

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.000808

Gnomad OTH AF: 0.0267

GnomAD3 exomes AF: 0.0124 AC: 3124 AN: 251316 Hom.: 240 AF XY: 0.00939 AC XY: 1275 AN XY: 135826

Gnomad AFR exome AF: 0.167

Gnomad AMR exome AF: 0.00795

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000229

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.000731

Gnomad OTH exome AF: 0.00587

GnomAD4 exome AF: 0.00550 AC: 8033 AN: 1461696 Hom.: 559 Cov.: 31 AF XY: 0.00494 AC XY: 3594 AN XY: 727164

Gnomad4 AFR exome AF: 0.174

Gnomad4 AMR exome AF: 0.00854

Gnomad4 ASJ exome AF: 0.0000765

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000301

Gnomad4 FIN exome AF: 0.0000374

Gnomad4 NFE exome AF: 0.00101

Gnomad4 OTH exome AF: 0.00980

GnomAD4 genome AF: 0.0477 AC: 7262 AN: 152280 Hom.: 569 Cov.: 32 AF XY: 0.0467 AC XY: 3480 AN XY: 74468

Gnomad4 AFR AF: 0.166

Gnomad4 AMR AF: 0.0157

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.000282

Gnomad4 NFE AF: 0.000808

Gnomad4 OTH AF: 0.0265

Alfa AF: 0.0121 Hom.: 69

Bravo AF: 0.0542

Asia WGS AF: 0.0110 AC: 38 AN: 3478

EpiCase AF: 0.000818

EpiControl AF: 0.00101

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

May 24, 2016

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The RAD50 c.3846T>C (p.Tyr1282Tyr) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. One in silico tool (MutationTaster) predicts a polymorphism outcome for this variant. This variant was found in 1833/121336 control chromosomes (146 homozygotes) at a frequency of 0.0151068, which is approximately 242 times the estimated maximal expected allele frequency of a pathogenic RAD50 variant (0.0000625), suggesting this variant is likely a benign polymorphism. It is a common polymorphism in African population with allele frequency of 16.52% (1717/10392 chromosomes) including 145 homozygotes. In addition, one clinical diagnostic laboratory classified this variant as benign. Taken together, this variant is classified as Benign. -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Benign:2

Nov 19, 2014

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as 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. -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nijmegen breakage syndrome-like disorder Benign:2

Jun 03, 2016

Counsyl

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 01, 2025

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

Mar 16, 2021

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Familial cancer of breast Benign:1

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.35
CADD	Benign	14
DANN	Benign	0.65

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: rs1804670; hg19: chr5-131977963; COSMIC: COSV99528774; COSMIC: COSV99528774;