rs104895050

Positions:

chr5-132618066-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_005732.4(RAD50):c.3165-4A>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00261 in 1,610,888 control chromosomes in the GnomAD database, including 42 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0019 ( 5 hom., cov: 32)

Exomes 𝑓: 0.0027 ( 37 hom. )

Consequence

RAD50
NM_005732.4 splice_region, intron

Scores

Splicing: ADA: 0.00007029

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7O:1

Conservation

PhyloP100: 0.0100

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.81).

BP6

Variant 5-132618066-A-T is Benign according to our data. Variant chr5-132618066-A-T is described in ClinVar as [Benign]. Clinvar id is 127003.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00188 (287/152324) while in subpopulation SAS AF= 0.0187 (90/4820). AF 95% confidence interval is 0.0156. There are 5 homozygotes in gnomad4. There are 173 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 5 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RAD50	NM_005732.4 linkuse as main transcript	c.3165-4A>T		splice_region_variant, intron_variant		ENST00000378823.8	NP_005723.2	Q92878-1A5D6Y3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RAD50	ENST00000378823.8 linkuse as main transcript	c.3165-4A>T		splice_region_variant, intron_variant		1	NM_005732.4	ENSP00000368100.4		Q92878-1
ENSG00000283782	ENST00000640655.2 linkuse as main transcript	c.2868-4A>T		splice_region_variant, intron_variant		5		ENSP00000491596.2		A0A1W2PQ90

Frequencies

GnomAD3 genomes

AF:

0.00188

AC:

286

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000217

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.0184

Gnomad FIN

AF:

0.00621

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00165

Gnomad OTH

AF:

0.00144

GnomAD3 exomes

AF:

0.00333

AC:

833

AN:

250358

Hom.:

AF XY:

0.00392

AC XY:

532

AN XY:

135636

show subpopulations

Gnomad AFR exome

AF:

0.000254

Gnomad AMR exome

AF:

0.000261

Gnomad ASJ exome

AF:

0.000199

Gnomad EAS exome

AF:

0.000217

Gnomad SAS exome

AF:

0.0164

Gnomad FIN exome

AF:

0.00518

Gnomad NFE exome

AF:

0.00157

Gnomad OTH exome

AF:

0.00346

GnomAD4 exome

AF:

0.00268

AC:

3916

AN:

1458564

Hom.:

Cov.:

AF XY:

0.00310

AC XY:

2253

AN XY:

725766

show subpopulations

Gnomad4 AFR exome

AF:

0.000449

Gnomad4 AMR exome

AF:

0.000268

Gnomad4 ASJ exome

AF:

0.000230

Gnomad4 EAS exome

AF:

0.000126

Gnomad4 SAS exome

AF:

0.0161

Gnomad4 FIN exome

AF:

0.00582

Gnomad4 NFE exome

AF:

0.00176

Gnomad4 OTH exome

AF:

0.00304

GnomAD4 genome

AF:

0.00188

AC:

287

AN:

152324

Hom.:

Cov.:

AF XY:

0.00232

AC XY:

173

AN XY:

74498

show subpopulations

Gnomad4 AFR

AF:

0.000216

Gnomad4 AMR

AF:

0.000327

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.0187

Gnomad4 FIN

AF:

0.00621

Gnomad4 NFE

AF:

0.00165

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.00138

Hom.:

Bravo

AF:

0.00100

Asia WGS

AF:

0.00838

AC:

AN:

3476

EpiCase

AF:

0.00104

EpiControl

AF:

0.00130

ClinVar

Significance: Benign

Submissions summary: Benign:7Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 26, 2013	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 17, 2020	Variant summary: RAD50 c.3165-4A>T alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0033 in 250358 control chromosomes in the gnomAD database, including 10 homozygotes. The observed variant frequency is approximately 53 fold of the estimated maximal expected allele frequency for a pathogenic variant in RAD50 causing Hereditary Breast and Ovarian Cancer phenotype (6.3e-05), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.3165-4A>T in individuals affected with Hereditary Breast and Ovarian Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign. Based on the evidence outlined above, the variant was classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Aug 26, 2021	- -

Hereditary cancer-predisposing syndrome

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 05, 2015	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. -

Familial cancer of breast

Benign:1

Benign, criteria provided, single submitter

clinical testing

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Jul 07, 2023

- -

Nijmegen breakage syndrome-like disorder

Benign:1

Benign, criteria provided, single submitter

clinical testing

Counsyl

Nov 03, 2016

- -

not provided

Other:1

not provided, no classification provided

literature only

Harris Lab, University of Minnesota

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

2.2

DANN

Benign

0.59

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000070

dbscSNV1_RF

Benign

0.0020

SpliceAI score (max)

0.030

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