Genetic Variant RAD1:p.Thr173Thr (chr5-34911601-C-T) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_ModerateBP6BP7BS2

The NM_002853.4(RAD1):c.519G>A(p.Thr173Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00108 in 1,614,126 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

Frequency

Genomes: 𝑓 0.00076 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0011 ( 2 hom. )

Consequence

RAD1
NM_002853.4 synonymous

Scores

Clinical Significance

Likely benign no assertion criteria provided B:1

Conservation

PhyloP100: -0.851

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.42).

BP6

Variant 5-34911601-C-T is Benign according to our data. Variant chr5-34911601-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 3042313.Status of the report is no_assertion_criteria_provided, 0 stars.

BP7

Synonymous conserved (PhyloP=-0.851 with no splicing effect.

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAD1	NM_002853.4 link	c.519G>A	p.Thr173Thr	synonymous_variant	Exon 4 of 6	ENST00000382038.7	NP_002844.1	O60671-1A0A024R045
RAD1	NR_026591.2 link	n.568G>A		non_coding_transcript_exon_variant	Exon 3 of 5
TTC23L	NR_169875.1 link	n.974-6763C>T		intron_variant	Intron 7 of 15
TTC23L	NR_169876.1 link	n.1048-6763C>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.519G>A	p.Thr173Thr	synonymous_variant	Exon 4 of 6	1	NM_002853.4	ENSP00000371469.2		O60671-1

Frequencies

GnomAD3 genomes

AF:

0.000749

AC:

114

AN:

152164

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000851

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00103

Gnomad FIN

AF:

0.0000943

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00121

Gnomad OTH

AF:

0.00143

GnomAD3 exomes

AF:

0.000974

AC:

245

AN:

251448

Hom.:

AF XY:

0.00105

AC XY:

143

AN XY:

135894

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000896

Gnomad ASJ exome

AF:

0.000496

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00121

Gnomad FIN exome

AF:

0.000185

Gnomad NFE exome

AF:

0.00144

Gnomad OTH exome

AF:

0.000651

GnomAD4 exome

AF:

0.00112

AC:

1631

AN:

1461844

Hom.:

Cov.:

AF XY:

0.00110

AC XY:

801

AN XY:

727228

show subpopulations

Gnomad4 AFR exome

AF:

0.000209

Gnomad4 AMR exome

AF:

0.000984

Gnomad4 ASJ exome

AF:

0.000651

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00116

Gnomad4 FIN exome

AF:

0.000168

Gnomad4 NFE exome

AF:

0.00125

Gnomad4 OTH exome

AF:

0.000762

GnomAD4 genome

AF:

0.000755

AC:

115

AN:

152282

Hom.:

Cov.:

AF XY:

0.000712

AC XY:

AN XY:

74458

show subpopulations

Gnomad4 AFR

AF:

0.000193

Gnomad4 AMR

AF:

0.000850

Gnomad4 ASJ

AF:

0.000576

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00104

Gnomad4 FIN

AF:

0.0000943

Gnomad4 NFE

AF:

0.00122

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.00102

Hom.:

Bravo

AF:

0.000669

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00191

EpiControl

AF:

0.00154

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

RAD1-related disorder

Benign:1

Jun 10, 2022

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely 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

BayesDel_noAF

Benign

-0.42

CADD

Benign

0.20

DANN

Benign

0.76

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