NM_005732.4:c.3879C>T

Variant names:

• chr5-132642304-C-T
• rs28903094
• NM_005732.4:c.3879C>T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6 BP7 BS2

The NM_005732.4(RAD50):​c.3879C>T​(p.Ile1293Ile) 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
• Publications: 7 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 -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 VariationId is 37384.
• BP7: Synonymous conserved (PhyloP=-1.48 with no splicing effect.
• BS2: High Homozygotes in GnomAd4 at 2 AD,AR gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAD50	NM_005732.4	MANE Select	c.3879C>T	p.Ile1293Ile	synonymous	Exon 25 of 25	NP_005723.2
	TH2LCRR	NR_132125.1		n.105-22G>A		intron	N/A
	TH2LCRR	NR_132126.1		n.175-4039G>A		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAD50	ENST00000378823.8	TSL:1 MANE Select	c.3879C>T	p.Ile1293Ile	synonymous	Exon 25 of 25	ENSP00000368100.4
	ENSG00000283782	ENST00000638452.2	TSL:5	c.3582C>T	p.Ile1194Ile	synonymous	Exon 27 of 27	ENSP00000492349.2
	RAD50	ENST00000533482.5	TSL:1	n.*3505C>T		non_coding_transcript_exon	Exon 25 of 25	ENSP00000431225.1

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

GnomAD2 exomes AF: 0.00249 AC: 626 AN: 251256 AF XY: 0.00242

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 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

African (AFR) AF: 0.000986 AC: 33 AN: 33474

American (AMR) AF: 0.00367 AC: 164 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.000115 AC: 3 AN: 26134

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39696

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86252

European-Finnish (FIN) AF: 0.000524 AC: 28 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00519 AC: 5769 AN: 1111856

Other (OTH) AF: 0.00339 AC: 205 AN: 60386

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

African (AFR) AF: 0.00123 AC: 51 AN: 41524

American (AMR) AF: 0.00373 AC: 57 AN: 15278

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.000378 AC: 4 AN: 10582

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00448 AC: 305 AN: 68020

Other (OTH) AF: 0.000945 AC: 2 AN: 2116

Alfa AF: 0.00376 Hom.: 2

Bravo AF: 0.00309

EpiCase AF: 0.00371

EpiControl AF: 0.00350

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	1	3	not provided (4)
-	-	2	Hereditary cancer-predisposing syndrome (2)
-	-	2	Nijmegen breakage syndrome-like disorder (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.60
CADD	Benign	3.7
DANN	Benign	0.76
PhyloP100		-1.5
Mutation Taster		=100/0	polymorphism

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