3-196471878-G-T

Position:

• chr3-196471878-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_152617.4(RNF168):​c.1657C>A​(p.Leu553Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: RNF168 NM_152617.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.855

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]

ACMG classification

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=0.16854441).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RNF168	NM_152617.4	c.1657C>A	p.Leu553Ile	missense_variant	6/6	ENST00000318037.3	NP_689830.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RNF168	ENST00000318037.3	c.1657C>A	p.Leu553Ile	missense_variant	6/6	1	NM_152617.4	ENSP00000320898.3
RNF168	ENST00000437070.1	n.*1229C>A		non_coding_transcript_exon_variant	5/5	2		ENSP00000396712.1
RNF168	ENST00000437070.1	n.*1229C>A		3_prime_UTR_variant	5/5	2		ENSP00000396712.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 30, 2023

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. This variant has not been reported in the literature in individuals affected with RNF168-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 553 of the RNF168 protein (p.Leu553Ile). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	9.9
DANN	Uncertain	0.98
DEOGEN2	Benign	0.081	T
Eigen	Benign	0.013
Eigen_PC	Benign	-0.031
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.68	T
M_CAP	Benign	0.0097	T
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.2	M
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.51	N
REVEL	Benign	0.053
Sift	Uncertain	0.019	D
Sift4G	Uncertain	0.027	D
Polyphen		0.91	P
Vest4		0.29
MutPred		0.15		Gain of glycosylation at S552 (P = 0.0169);
MVP		0.35
MPC		0.081
ClinPred		0.26	T
GERP RS		3.2
Varity_R		0.071
gMVP		0.050

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-196198749; COSMIC: COSV100534955; COSMIC: COSV100534955;