rs28903091

Positions:

chr5-132588018-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The ENST00000378823.8(RAD50):c.980G>A(p.Arg327His) variant causes a missense change. The variant allele was found at a frequency of 0.00257 in 1,611,958 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R327C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0022 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0026 ( 24 hom. )

Consequence

RAD50
ENST00000378823.8 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:10

Conservation

PhyloP100: 6.21

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0049374104).

BP6

Variant 5-132588018-G-A is Benign according to our data. Variant chr5-132588018-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 37380.We mark this variant Likely_benign, oryginal submissions are: {Benign=5, Uncertain_significance=2, Likely_benign=4}.

BS1

Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.00261 (3806/1459672) while in subpopulation SAS AF= 0.00797 (687/86196). AF 95% confidence interval is 0.00748. There are 24 homozygotes in gnomad4_exome. There are 2092 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 24 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RAD50	NM_005732.4 linkuse as main transcript	c.980G>A	p.Arg327His	missense_variant	7/25	ENST00000378823.8	NP_005723.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RAD50	ENST00000378823.8 linkuse as main transcript	c.980G>A	p.Arg327His	missense_variant	7/25	1	NM_005732.4	ENSP00000368100	P1	Q92878-1

Frequencies

GnomAD3 genomes

AF:

0.00225

AC:

342

AN:

152168

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000338

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000982

Gnomad ASJ

AF:

0.0164

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00684

Gnomad FIN

AF:

0.000566

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.00300

Gnomad OTH

AF:

0.00334

GnomAD3 exomes

AF:

0.00346

AC:

865

AN:

249856

Hom.:

AF XY:

0.00394

AC XY:

533

AN XY:

135142

show subpopulations

Gnomad AFR exome

AF:

0.000433

Gnomad AMR exome

AF:

0.00153

Gnomad ASJ exome

AF:

0.0149

Gnomad EAS exome

AF:

0.000218

Gnomad SAS exome

AF:

0.00802

Gnomad FIN exome

AF:

0.000555

Gnomad NFE exome

AF:

0.00326

Gnomad OTH exome

AF:

0.00460

GnomAD4 exome

AF:

0.00261

AC:

3806

AN:

1459672

Hom.:

Cov.:

AF XY:

0.00288

AC XY:

2092

AN XY:

726296

show subpopulations

Gnomad4 AFR exome

AF:

0.000329

Gnomad4 AMR exome

AF:

0.00168

Gnomad4 ASJ exome

AF:

0.0156

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.00797

Gnomad4 FIN exome

AF:

0.000731

Gnomad4 NFE exome

AF:

0.00208

Gnomad4 OTH exome

AF:

0.00376

GnomAD4 genome

AF:

0.00224

AC:

341

AN:

152286

Hom.:

Cov.:

AF XY:

0.00219

AC XY:

163

AN XY:

74458

show subpopulations

Gnomad4 AFR

AF:

0.000337

Gnomad4 AMR

AF:

0.000980

Gnomad4 ASJ

AF:

0.0164

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00685

Gnomad4 FIN

AF:

0.000566

Gnomad4 NFE

AF:

0.00300

Gnomad4 OTH

AF:

0.00331

Alfa

AF:

0.00368

Hom.:

Bravo

AF:

0.00225

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.00156

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00337

AC:

ExAC

AF:

0.00350

AC:

425

Asia WGS

AF:

0.00260

AC:

AN:

3470

EpiCase

AF:

0.00338

EpiControl

AF:

0.00338

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:10

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Benign:4

Likely benign, criteria provided, single submitter	clinical testing	GeneKor MSA	Aug 01, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 25, 2014	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. -
Benign, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	May 03, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not provided

Uncertain:1Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 31, 2019	This variant is associated with the following publications: (PMID: 29928469, 16385572, 27153395, 20805886, 31159747) -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	RAD50: BP4, BS2 -

Nijmegen breakage syndrome-like disorder

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Jul 05, 2016	- -
Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Jul 28, 2021	- -

not specified

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jan 04, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jun 10, 2021	- -

RAD50-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 21, 2020

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.097

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.39

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.28

.;.;.;T;T

Eigen

Pathogenic

0.69

Eigen_PC

Pathogenic

0.69

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.91

.;.;D;D;D

M_CAP

Benign

0.0064

MetaRNN

Benign

0.0049

T;T;T;T;T

MetaSVM

Benign

-1.2

MutationAssessor

Uncertain

2.1

.;.;.;M;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Benign

0.41

PROVEAN

Uncertain

-2.5

.;.;.;.;N

REVEL

Benign

0.21

Sift

Benign

0.063

.;.;.;.;T

Sift4G

Uncertain

0.022

.;.;.;D;D

Polyphen

0.99

.;.;.;D;.

Vest4

0.23

MVP

0.71

ClinPred

0.032

GERP RS

5.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.27

gMVP

0.17

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over