3-196472333-G-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_152617.4(RNF168):c.1202C>A(p.Pro401Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.586 in 1,613,568 control chromosomes in the GnomAD database, including 287,146 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P401L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.50 ( 20697 hom., cov: 32)

Exomes 𝑓: 0.59 ( 266449 hom. )

Consequence

RNF168
NM_152617.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 2.44

Publications

39 publications found

Variant links:

Genes affected

RNF168 (HGNC:26661): (ring finger protein 168) This gene encodes an E3 ubiquitin ligase protein that contains a RING finger, a motif present in a variety of functionally distinct proteins and known to be involved in protein-DNA and protein-protein interactions. The protein is involved in DNA double-strand break (DSB) repair. Mutations in this gene result in Riddle syndrome. [provided by RefSeq, Sep 2011]

RNF168 Gene-Disease associations (from GenCC):

RIDDLE syndrome
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet, ClinGen, G2P

RNF168 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=3.641032E-5).

BP6

Variant 3-196472333-G-T is Benign according to our data. Variant chr3-196472333-G-T is described in ClinVar as Benign. ClinVar VariationId is 403381.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.609 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RNF168	NM_152617.4 link	c.1202C>A	p.Pro401Gln	missense_variant	Exon 6 of 6	ENST00000318037.3	NP_689830.2	Q8IYW5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
RNF168	ENST00000318037.3 link	c.1202C>A	p.Pro401Gln	missense_variant	Exon 6 of 6	1	NM_152617.4	ENSP00000320898.3	Q8IYW5
RNF168	ENST00000437070.1 link	n.*774C>A		non_coding_transcript_exon_variant	Exon 5 of 5	2		ENSP00000396712.1	F8WD60
RNF168	ENST00000437070.1 link	n.*774C>A		3_prime_UTR_variant	Exon 5 of 5	2		ENSP00000396712.1	F8WD60

Frequencies

GnomAD3 genomes

AF:

0.499

AC:

75789

AN:

151904

Hom.:

20700

Cov.:

show subpopulations

Gnomad AFR

AF:

0.301

Gnomad AMI

AF:

0.647

Gnomad AMR

AF:

0.441

Gnomad ASJ

AF:

0.617

Gnomad EAS

AF:

0.174

Gnomad SAS

AF:

0.597

Gnomad FIN

AF:

0.672

Gnomad MID

AF:

0.564

Gnomad NFE

AF:

0.614

Gnomad OTH

AF:

0.511

GnomAD2 exomes

AF:

0.536

AC:

134718

AN:

251322

AF XY:

0.554

show subpopulations

Gnomad AFR exome

AF:

0.290

Gnomad AMR exome

AF:

0.401

Gnomad ASJ exome

AF:

0.616

Gnomad EAS exome

AF:

0.165

Gnomad FIN exome

AF:

0.661

Gnomad NFE exome

AF:

0.618

Gnomad OTH exome

AF:

0.573

GnomAD4 exome

AF:

0.595

AC:

869575

AN:

1461548

Hom.:

266449

Cov.:

AF XY:

0.598

AC XY:

434639

AN XY:

727064

show subpopulations

African (AFR)

AF:

0.290

AC:

9711

AN:

33464

American (AMR)

AF:

0.406

AC:

18145

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.614

AC:

16054

AN:

26130

East Asian (EAS)

AF:

0.162

AC:

6443

AN:

39700

South Asian (SAS)

AF:

0.621

AC:

53572

AN:

86250

European-Finnish (FIN)

AF:

0.663

AC:

35408

AN:

53410

Middle Eastern (MID)

AF:

0.611

AC:

3522

AN:

5768

European-Non Finnish (NFE)

AF:

0.622

AC:

691719

AN:

1111728

Other (OTH)

AF:

0.580

AC:

35001

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

19255

38510

57766

77021

96276

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

18270

36540

54810

73080

91350

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.499

AC:

75788

AN:

152020

Hom.:

20697

Cov.:

AF XY:

0.499

AC XY:

37046

AN XY:

74298

show subpopulations

African (AFR)

AF:

0.301

AC:

12456

AN:

41448

American (AMR)

AF:

0.441

AC:

6733

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.617

AC:

2142

AN:

3470

East Asian (EAS)

AF:

0.174

AC:

898

AN:

5170

South Asian (SAS)

AF:

0.597

AC:

2878

AN:

4818

European-Finnish (FIN)

AF:

0.672

AC:

7107

AN:

10574

Middle Eastern (MID)

AF:

0.555

AC:

162

AN:

292

European-Non Finnish (NFE)

AF:

0.614

AC:

41748

AN:

67956

Other (OTH)

AF:

0.510

AC:

1075

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1827

3654

5482

7309

9136

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

678

1356

2034

2712

3390

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.571

Hom.:

110727

Bravo

AF:

0.468

TwinsUK

AF:

0.619

AC:

2297

ALSPAC

AF:

0.624

AC:

2405

ESP6500AA

AF:

0.312

AC:

1373

ESP6500EA

AF:

0.623

AC:

5354

ExAC

AF:

0.540

AC:

65614

Asia WGS

AF:

0.397

AC:

1380

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

RIDDLE syndrome

Benign:2

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 07, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:1

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.71

BayesDel_noAF

Benign

-0.65

CADD

Benign

(source)

DANN

Benign

0.88

DEOGEN2

Benign

0.013

Eigen

Benign

-0.21

Eigen_PC

Benign

-0.29

FATHMM_MKL

Benign

0.29

LIST_S2

Benign

0.67

MetaRNN

Benign

0.000036

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.4

PhyloP100

2.4

PrimateAI

Benign

0.22

PROVEAN

Benign

-1.0

REVEL

Benign

0.059

Sift

Benign

0.058

Sift4G

Benign

0.25

Polyphen

0.80

Vest4

0.29

MPC

0.21

ClinPred

0.016

GERP RS

4.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.044

gMVP

0.069

Mutation Taster

=96/4

polymorphism (auto)

(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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over