rs1804670

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -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:9
• Conservation: PhyloP100: 0.0570
• Publications: 8 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]

ENSG00000283782 (HGNC:):

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

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

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.3846T>C	p.Tyr1282Tyr	synonymous	Exon 25 of 25	NP_005723.2
	TH2LCRR	NR_132125.1		n.116A>G		non_coding_transcript_exon	Exon 2 of 3
	TH2LCRR	NR_132126.1		n.175-4006A>G		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAD50	ENST00000378823.8	TSL:1 MANE Select	c.3846T>C	p.Tyr1282Tyr	synonymous	Exon 25 of 25	ENSP00000368100.4
	ENSG00000283782	ENST00000638452.2	TSL:5	c.3549T>C	p.Tyr1183Tyr	synonymous	Exon 27 of 27	ENSP00000492349.2
	TH2LCRR	ENST00000458509.1	TSL:1	n.116A>G		non_coding_transcript_exon	Exon 2 of 3

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

GnomAD2 exomes AF: 0.0124 AC: 3124 AN: 251316 AF XY: 0.00939

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 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

African (AFR) AF: 0.174 AC: 5820 AN: 33470

American (AMR) AF: 0.00854 AC: 382 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.0000765 AC: 2 AN: 26134

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39698

South Asian (SAS) AF: 0.000301 AC: 26 AN: 86252

European-Finnish (FIN) AF: 0.0000374 AC: 2 AN: 53418

Middle Eastern (MID) AF: 0.0139 AC: 80 AN: 5768

European-Non Finnish (NFE) AF: 0.00101 AC: 1128 AN: 1111848

Other (OTH) AF: 0.00980 AC: 592 AN: 60392

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

African (AFR) AF: 0.166 AC: 6902 AN: 41530

American (AMR) AF: 0.0157 AC: 240 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4812

European-Finnish (FIN) AF: 0.000282 AC: 3 AN: 10620

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.000808 AC: 55 AN: 68034

Other (OTH) AF: 0.0265 AC: 56 AN: 2116

Alfa AF: 0.0108 Hom.: 84

Bravo AF: 0.0542

Asia WGS AF: 0.0110 AC: 38 AN: 3478

EpiCase AF: 0.000818

EpiControl AF: 0.00101

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Hereditary cancer-predisposing syndrome (3)
-	-	2	Nijmegen breakage syndrome-like disorder (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	-0.35
CADD	Benign	14
DANN	Benign	0.65
PhyloP100		0.057
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: rs1804670; hg19: chr5-131977963; COSMIC: COSV99528774;