8-124486139-A-G

Position:

• chr8-124486139-A-G

Variant summary

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

The NM_007218.4(RNF139):​c.490A>G​(p.Ile164Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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: not found (cov: 32)
• Consequence: RNF139 NM_007218.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.93

Genes affected

RNF139 (HGNC:17023): (ring finger protein 139) The protein encoded by this gene is a multi-membrane spanning protein containing a RING-H2 finger. This protein is located in the endoplasmic reticulum, and has been shown to possess ubiquitin ligase activity. This gene was found to be interrupted by a t(3:8) translocation in a family with hereditary renal and non-medulary thyroid cancer. Studies of the Drosophila counterpart suggested that this protein may interact with tumor suppressor protein VHL, as well as with COPS5/JAB1, a protein responsible for the degradation of tumor suppressor CDKN1B/P27KIP. [provided by RefSeq, Jul 2008]

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=0.1160464).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RNF139	NM_007218.4	c.490A>G	p.Ile164Val	missense_variant	2/2	ENST00000303545.4	NP_009149.2
RNF139	XM_047421310.1	c.109A>G	p.Ile37Val	missense_variant	3/3		XP_047277266.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RNF139	ENST00000303545.4	c.490A>G	p.Ile164Val	missense_variant	2/2	1	NM_007218.4	ENSP00000304051	P1
RNF139	ENST00000517684.2	c.109A>G	p.Ile37Val	missense_variant	2/2	3		ENSP00000429836

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 specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 15, 2021

The c.490A>G (p.I164V) alteration is located in exon 2 (coding exon 2) of the RNF139 gene. This alteration results from a A to G substitution at nucleotide position 490, causing the isoleucine (I) at amino acid position 164 to be replaced by a valine (V). 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	0.068
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	16
DANN	Benign	0.95
DEOGEN2	Benign	0.031	T;.
Eigen	Benign	-0.20
Eigen_PC	Benign	-0.028
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.77	T;T
M_CAP	Benign	0.0029	T
MetaRNN	Benign	0.12	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.28	N;.
MutationTaster	Benign	0.67	N
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.44	N;N
REVEL	Benign	0.031
Sift	Benign	0.20	T;T
Sift4G	Benign	0.31	T;T
Polyphen		0.023	B;.
Vest4		0.16
MutPred		0.31		Loss of helix (P = 0.1299);.;
MVP		0.43
MPC		0.45
ClinPred		0.36	T
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.027
gMVP		0.42

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: chr8-125498380;