Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1PM2PP3_Moderate

The NM_005732.4(RAD50):c.3463T>G(p.Tyr1155Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y1155C) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

RAD50
NM_005732.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.66

Publications

0 publications found

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 was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 34 uncertain in NM_005732.4

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.93

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.3463T>G	p.Tyr1155Asp	missense	Exon 22 of 25	NP_005723.2
	TH2LCRR	NR_132124.1		n.153+970A>C		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
RAD50	ENST00000378823.8	TSL:1 MANE Select	c.3463T>G	p.Tyr1155Asp	missense	Exon 22 of 25	ENSP00000368100.4
ENSG00000283782	ENST00000638452.2	TSL:5	c.3166T>G	p.Tyr1056Asp	missense	Exon 24 of 27	ENSP00000492349.2
RAD50	ENST00000533482.5	TSL:1	n.*3089T>G		non_coding_transcript_exon	Exon 22 of 25	ENSP00000431225.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hereditary cancer-predisposing syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.51

BayesDel_noAF

Pathogenic

0.49

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.64

Eigen

Pathogenic

0.88

Eigen_PC

Pathogenic

0.78

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.91

M_CAP

Benign

0.059

MetaRNN

Pathogenic

0.93

MetaSVM

Benign

-0.98

MutationAssessor

Pathogenic

3.7

PhyloP100

7.7

PrimateAI

Pathogenic

0.88

REVEL

Pathogenic

0.78

Sift4G

Pathogenic

0.0010

Polyphen

1.0

Vest4

0.90

MutPred

0.78

Gain of disorder (P = 0.017)

MVP

0.82

ClinPred

1.0

GERP RS

5.9

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.7

Varity_R

0.90

gMVP

0.98

Mutation Taster

=30/70

disease causing

(source)

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

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5-132637188-T-G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over