9-137220642-G-C

Position:

• chr9-137220642-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_031297.7(RNF208):​c.571C>G​(p.Arg191Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,460,250 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: RNF208 NM_031297.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.15

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.86

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RNF208	NM_031297.7	c.571C>G	p.Arg191Gly	missense_variant	2/2	ENST00000391553.3	NP_112587.2
RNF208	NM_001388297.1	c.571C>G	p.Arg191Gly	missense_variant	2/2		NP_001375226.1
RNF208	NM_001388298.1	c.571C>G	p.Arg191Gly	missense_variant	2/2		NP_001375227.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RNF208	ENST00000391553.3	c.571C>G	p.Arg191Gly	missense_variant	2/2	6	NM_031297.7	ENSP00000375397.1
RNF208	ENST00000392827.2	c.571C>G	p.Arg191Gly	missense_variant	2/2	5		ENSP00000376572.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460250 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 726430

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 07, 2023

The c.571C>G (p.R191G) alteration is located in exon 1 (coding exon 1) of the RNF208 gene. This alteration results from a C to G substitution at nucleotide position 571, causing the arginine (R) at amino acid position 191 to be replaced by a glycine (G). 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	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.0
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.22	T;T
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.87	D;.
M_CAP	Pathogenic	0.65	D
MetaRNN	Pathogenic	0.86	D;D
MetaSVM	Benign	-0.62	T
MutationAssessor	Benign	1.4	L;L
PrimateAI	Uncertain	0.79	T
PROVEAN	Uncertain	-2.6	D;D
REVEL	Uncertain	0.47
Sift	Uncertain	0.013	D;D
Sift4G	Uncertain	0.022	D;D
Polyphen		1.0	D;D
Vest4		0.82
MutPred		0.55		Loss of stability (P = 0.0287);Loss of stability (P = 0.0287);
MVP		0.22
MPC		0.94
ClinPred		0.97	D
GERP RS		3.2
Varity_R		0.44
gMVP		0.71

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: chr9-140115094;