Genetic Variant RAD1:p.Gly114Asp (chr5-34911779-C-T) – ACMG Classification: Benign (-9 pts)

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_002853.4(RAD1):c.341G>A(p.Gly114Asp) variant causes a missense change. The variant allele was found at a frequency of 0.00646 in 1,614,138 control chromosomes in the GnomAD database, including 45 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.0058 ( 4 hom., cov: 32)

Exomes 𝑓: 0.0065 ( 41 hom. )

Consequence

RAD1
NM_002853.4 missense

Scores

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: 5.81

Variant links:

Genes affected

RAD1 (HGNC:9806): (RAD1 checkpoint DNA exonuclease) This gene encodes a component of a heterotrimeric cell cycle checkpoint complex, known as the 9-1-1 complex, that is activated to stop cell cycle progression in response to DNA damage or incomplete DNA replication. The 9-1-1 complex is recruited by RAD17 to affected sites where it may attract specialized DNA polymerases and other DNA repair effectors. Alternatively spliced transcript variants of this gene have been described. [provided by RefSeq, Jan 2009]

RAD1 links:

TTC23L (HGNC:26355): (tetratricopeptide repeat domain 23 like) Predicted to be located in cytoplasm; microtubule cytoskeleton; and midbody. [provided by Alliance of Genome Resources, Apr 2022]

TTC23L links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009761691).

BP6

Variant 5-34911779-C-T is Benign according to our data. Variant chr5-34911779-C-T is described in ClinVar as [Benign]. Clinvar id is 3037412.Status of the report is no_assertion_criteria_provided, 0 stars.

BS2

High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAD1	NM_002853.4 link	c.341G>A	p.Gly114Asp	missense_variant	Exon 4 of 6	ENST00000382038.7	NP_002844.1	O60671-1A0A024R045
RAD1	NR_026591.2 link	n.390G>A		non_coding_transcript_exon_variant	Exon 3 of 5
TTC23L	NR_169875.1 link	n.974-6585C>T		intron_variant	Intron 7 of 15
TTC23L	NR_169876.1 link	n.1048-6585C>T		intron_variant	Intron 7 of 15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAD1	ENST00000382038.7 link	c.341G>A	p.Gly114Asp	missense_variant	Exon 4 of 6	1	NM_002853.4	ENSP00000371469.2		O60671-1

Frequencies

GnomAD3 genomes

AF:

0.00586

AC:

891

AN:

152170

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00118

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.00478

Gnomad ASJ

AF:

0.0135

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.0162

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00785

Gnomad OTH

AF:

0.00574

GnomAD3 exomes

AF:

0.00632

AC:

1590

AN:

251414

Hom.:

AF XY:

0.00606

AC XY:

823

AN XY:

135878

show subpopulations

Gnomad AFR exome

AF:

0.000800

Gnomad AMR exome

AF:

0.00500

Gnomad ASJ exome

AF:

0.0146

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000882

Gnomad FIN exome

AF:

0.0177

Gnomad NFE exome

AF:

0.00703

Gnomad OTH exome

AF:

0.00799

GnomAD4 exome

AF:

0.00652

AC:

9530

AN:

1461850

Hom.:

Cov.:

AF XY:

0.00649

AC XY:

4721

AN XY:

727218

show subpopulations

Gnomad4 AFR exome

AF:

0.000747

Gnomad4 AMR exome

AF:

0.00510

Gnomad4 ASJ exome

AF:

0.0136

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00115

Gnomad4 FIN exome

AF:

0.0166

Gnomad4 NFE exome

AF:

0.00673

Gnomad4 OTH exome

AF:

0.00734

GnomAD4 genome

AF:

0.00584

AC:

890

AN:

152288

Hom.:

Cov.:

AF XY:

0.00635

AC XY:

473

AN XY:

74468

show subpopulations

Gnomad4 AFR

AF:

0.00118

Gnomad4 AMR

AF:

0.00477

Gnomad4 ASJ

AF:

0.0135

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.0162

Gnomad4 NFE

AF:

0.00785

Gnomad4 OTH

AF:

0.00568

Alfa

AF:

0.00707

Hom.:

Bravo

AF:

0.00484

TwinsUK

AF:

0.00755

AC:

ALSPAC

AF:

0.00493

AC:

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.00686

AC:

ExAC

AF:

0.00562

AC:

682

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00649

EpiControl

AF:

0.00699

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

RAD1-related disorder

Benign:1

Nov 04, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

Pathogenic

0.85

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.23

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.14

T;T

Eigen

Uncertain

0.56

Eigen_PC

Uncertain

0.54

FATHMM_MKL

Uncertain

0.97

LIST_S2

Benign

0.82

.;T

MetaRNN

Benign

0.0098

T;T

MetaSVM

Benign

-0.91

MutationAssessor

Uncertain

2.8

M;M

PrimateAI

Uncertain

0.72

PROVEAN

Pathogenic

-5.2

D;D

REVEL

Uncertain

0.30

Sift

Uncertain

0.0080

D;D

Sift4G

Uncertain

0.0090

D;D

Polyphen

1.0

D;D

Vest4

0.57

MVP

0.50

MPC

0.50

ClinPred

0.029

GERP RS

5.0

Varity_R

0.79

gMVP

0.87

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

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over