22-31196949-C-G

Position:

• chr22-31196949-C-G

Variant summary

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

The NM_152267.4(RNF185):​c.322C>G​(p.Pro108Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: RNF185 NM_152267.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.50

Genes affected

RNF185 (HGNC:26783): (ring finger protein 185) Enables ubiquitin binding activity; ubiquitin protein ligase activity; and ubiquitin-like protein conjugating enzyme binding activity. Involved in positive regulation of ERAD pathway; protein autoubiquitination; and ubiquitin-dependent ERAD pathway. Located in endoplasmic reticulum. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RNF185	NM_152267.4	c.322C>G	p.Pro108Ala	missense_variant	5/7	ENST00000326132.11	NP_689480.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RNF185	ENST00000326132.11	c.322C>G	p.Pro108Ala	missense_variant	5/7	1	NM_152267.4	ENSP00000320508	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

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

Dec 08, 2023

The c.322C>G (p.P108A) alteration is located in exon 5 (coding exon 4) of the RNF185 gene. This alteration results from a C to G substitution at nucleotide position 322, causing the proline (P) at amino acid position 108 to be replaced by an alanine (A). 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	0.66
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.14	T;T
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	.;D
M_CAP	Pathogenic	0.37	D
MetaRNN	Uncertain	0.53	D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.8	M;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.80	T
PROVEAN	Pathogenic	-7.8	D;.
REVEL	Pathogenic	0.66
Sift	Pathogenic	0.0	D;.
Sift4G	Uncertain	0.041	D;D
Polyphen		0.98	D;.
Vest4		0.54
MutPred		0.23		Loss of catalytic residue at P107 (P = 0.0116);Loss of catalytic residue at P107 (P = 0.0116);
MVP		0.82
MPC		1.0
ClinPred		1.0	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.83
gMVP		0.45

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: chr22-31592935;