Variant 9-137221119-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_031297.7(RNF208):c.94G>A(p.Ala32Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000615 in 1,604,396 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 𝑓 0.00043 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00063 ( 0 hom. )

Consequence

RNF208
NM_031297.7 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.58

Variant links:

Genes affected

RNF208 (HGNC:25420): (ring finger protein 208) Enables ubiquitin-protein transferase activity. Involved in protein autoubiquitination. Located in cytosol and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

RNF208 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.017645746).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RNF208	NM_031297.7 linkuse as main transcript	c.94G>A	p.Ala32Thr	missense_variant	2/2	ENST00000391553.3	NP_112587.2	Q9H0X6
RNF208	NM_001388297.1 linkuse as main transcript	c.94G>A	p.Ala32Thr	missense_variant	2/2		NP_001375226.1
RNF208	NM_001388298.1 linkuse as main transcript	c.94G>A	p.Ala32Thr	missense_variant	2/2		NP_001375227.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RNF208	ENST00000391553.3 linkuse as main transcript	c.94G>A	p.Ala32Thr	missense_variant	2/2	6	NM_031297.7	ENSP00000375397.1		Q9H0X6
RNF208	ENST00000392827.2 linkuse as main transcript	c.94G>A	p.Ala32Thr	missense_variant	2/2	5		ENSP00000376572.1		Q9H0X6

Frequencies

GnomAD3 genomes

AF:

0.000428

AC:

AN:

151926

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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:

0.000809

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000462

AC:

109

AN:

236120

Hom.:

AF XY:

0.000403

AC XY:

AN XY:

128904

show subpopulations

Gnomad AFR exome

AF:

0.000210

Gnomad AMR exome

AF:

0.000687

Gnomad ASJ exome

AF:

0.000105

Gnomad EAS exome

AF:

0.000114

Gnomad SAS exome

AF:

0.0000343

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000685

Gnomad OTH exome

AF:

0.00105

GnomAD4 exome

AF:

0.000634

AC:

921

AN:

1452352

Hom.:

Cov.:

AF XY:

0.000577

AC XY:

416

AN XY:

721524

show subpopulations

Gnomad4 AFR exome

AF:

0.0000899

Gnomad4 AMR exome

AF:

0.000750

Gnomad4 ASJ exome

AF:

0.0000387

Gnomad4 EAS exome

AF:

0.0000507

Gnomad4 SAS exome

AF:

0.0000470

Gnomad4 FIN exome

AF:

0.0000194

Gnomad4 NFE exome

AF:

0.000753

Gnomad4 OTH exome

AF:

0.000717

GnomAD4 genome

AF:

0.000428

AC:

AN:

152044

Hom.:

Cov.:

AF XY:

0.000350

AC XY:

AN XY:

74326

show subpopulations

Gnomad4 AFR

AF:

0.000193

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000809

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000591

Hom.:

Bravo

AF:

0.000453

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000603

AC:

ExAC

AF:

0.000450

AC:

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

Jun 11, 2021

The c.94G>A (p.A32T) alteration is located in exon 1 (coding exon 1) of the RNF208 gene. This alteration results from a G to A substitution at nucleotide position 94, causing the alanine (A) at amino acid position 32 to be replaced by a threonine (T). 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

0.26

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.64

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.025

T;T

Eigen

Benign

-0.33

Eigen_PC

Benign

-0.15

FATHMM_MKL

Benign

0.56

LIST_S2

Benign

0.72

T;.

M_CAP

Benign

0.042

MetaRNN

Benign

0.018

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.0

N;N

PrimateAI

Pathogenic

0.84

PROVEAN

Benign

-0.25

N;N

REVEL

Benign

0.032

Sift

Benign

0.28

T;T

Sift4G

Benign

0.80

T;T

Polyphen

0.0020

B;B

Vest4

0.18

MVP

0.043

MPC

0.23

ClinPred

0.012

GERP RS

3.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.082

gMVP

0.31

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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