Genetic Variant RAD50:c.3753-321T>G (chr5-132641857-T-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_005732.4(RAD50):c.3753-321T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0522 in 296,930 control chromosomes in the GnomAD database, including 2,063 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.087 ( 1815 hom., cov: 32)

Exomes 𝑓: 0.016 ( 248 hom. )

Consequence

RAD50
NM_005732.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.221

Variant links:

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]

RAD50 links:

ENSG00000283782 (HGNC:):

ENSG00000283782 links:

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

TH2LCRR links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.77).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.289 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
RAD50	NM_005732.4 link	c.3753-321T>G	intron_variant	Intron 24 of 24	ENST00000378823.8	NP_005723.2	Q92878-1A5D6Y3
TH2LCRR	NR_132125.1 link	n.189+341A>C	intron_variant	Intron 2 of 2
TH2LCRR	NR_132126.1 link	n.175-3592A>C	intron_variant	Intron 1 of 1
TH2LCRR	NR_132124.1 link	n.-67A>C	upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAD50	ENST00000378823.8 link	c.3753-321T>G		intron_variant	Intron 24 of 24	1	NM_005732.4	ENSP00000368100.4		Q92878-1
ENSG00000283782	ENST00000640655.2 link	c.3456-321T>G		intron_variant	Intron 25 of 25	5		ENSP00000491596.2		A0A1W2PQ90

Frequencies

GnomAD3 genomes

AF:

0.0863

AC:

13130

AN:

152158

Hom.:

1803

Cov.:

show subpopulations

Gnomad AFR

AF:

0.293

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0348

Gnomad ASJ

AF:

0.00259

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.0114

Gnomad FIN

AF:

0.000282

Gnomad MID

AF:

0.0443

Gnomad NFE

AF:

0.00413

Gnomad OTH

AF:

0.0589

GnomAD4 exome

AF:

0.0161

AC:

2323

AN:

144654

Hom.:

248

Cov.:

AF XY:

0.0147

AC XY:

1085

AN XY:

73908

show subpopulations

Gnomad4 AFR exome

AF:

0.285

Gnomad4 AMR exome

AF:

0.0281

Gnomad4 ASJ exome

AF:

0.00120

Gnomad4 EAS exome

AF:

0.0000999

Gnomad4 SAS exome

AF:

0.00927

Gnomad4 FIN exome

AF:

0.000164

Gnomad4 NFE exome

AF:

0.00373

Gnomad4 OTH exome

AF:

0.0228

GnomAD4 genome

AF:

0.0865

AC:

13177

AN:

152276

Hom.:

1815

Cov.:

AF XY:

0.0835

AC XY:

6219

AN XY:

74482

show subpopulations

Gnomad4 AFR

AF:

0.293

Gnomad4 AMR

AF:

0.0348

Gnomad4 ASJ

AF:

0.00259

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.0116

Gnomad4 FIN

AF:

0.000282

Gnomad4 NFE

AF:

0.00412

Gnomad4 OTH

AF:

0.0582

Alfa

AF:

0.0121

Hom.:

Bravo

AF:

0.0998

Asia WGS

AF:

0.0260

AC:

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.77

CADD

Benign

7.6

DANN

Benign

0.77

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over