Variant 11-74749100-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001098638.2(RNF169):c.220C>T(p.Pro74Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000137 in 1,427,194 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00014 ( 0 hom. )

Consequence

RNF169
NM_001098638.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.645

Variant links:

Genes affected

RNF169 (HGNC:26961): (ring finger protein 169) Enables K63-linked polyubiquitin modification-dependent protein binding activity and nucleosome binding activity. Involved in cellular response to DNA damage stimulus and negative regulation of double-strand break repair. Located in cytosol; nuclear lumen; and site of double-strand break. [provided by Alliance of Genome Resources, Apr 2022]

RNF169 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.15842536).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RNF169	NM_001098638.2 linkuse as main transcript	c.220C>T	p.Pro74Ser	missense_variant	1/6	ENST00000299563.5	NP_001092108.1
RNF169	XM_011544889.4 linkuse as main transcript	c.220C>T	p.Pro74Ser	missense_variant	1/6		XP_011543191.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RNF169	ENST00000299563.5 linkuse as main transcript	c.220C>T	p.Pro74Ser	missense_variant	1/6	1	NM_001098638.2	ENSP00000299563	P1

Frequencies

GnomAD3 genomes

AF:

0.000105

AC:

AN:

151702

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000484

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000656

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000192

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000719

AC:

AN:

69520

Hom.:

AF XY:

0.0000739

AC XY:

AN XY:

40604

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000324

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000373

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000140

AC:

179

AN:

1275492

Hom.:

Cov.:

AF XY:

0.000115

AC XY:

AN XY:

626822

show subpopulations

Gnomad4 AFR exome

AF:

0.0000769

Gnomad4 AMR exome

AF:

0.000171

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000166

Gnomad4 OTH exome

AF:

0.0000768

GnomAD4 genome

AF:

0.000105

AC:

AN:

151702

Hom.:

Cov.:

AF XY:

0.000135

AC XY:

AN XY:

74102

show subpopulations

Gnomad4 AFR

AF:

0.0000484

Gnomad4 AMR

AF:

0.0000656

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000192

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000214

Hom.:

Bravo

AF:

0.000110

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 21, 2023

The c.220C>T (p.P74S) alteration is located in exon 1 (coding exon 1) of the RNF169 gene. This alteration results from a C to T substitution at nucleotide position 220, causing the proline (P) at amino acid position 74 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.066

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.32

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.0068

Eigen

Benign

-0.91

Eigen_PC

Benign

-0.84

FATHMM_MKL

Benign

0.12

LIST_S2

Benign

0.34

M_CAP

Pathogenic

0.60

MetaRNN

Benign

0.16

MetaSVM

Benign

-0.95

MutationAssessor

Benign

0.050

MutationTaster

Benign

0.99

PrimateAI

Pathogenic

0.82

PROVEAN

Benign

0.59

REVEL

Benign

0.11

Sift

Benign

0.058

Sift4G

Benign

0.57

Polyphen

0.0040

Vest4

0.26

MutPred

0.39

Loss of catalytic residue at P74 (P = 0.0074);

MVP

0.56

MPC

0.21

ClinPred

0.072

GERP RS

0.71

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.040

gMVP

0.27

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