8-124487255-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.1606A>G(p.Lys536Glu) 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. 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: 2.87

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=0.19138971).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RNF139	NM_007218.4	c.1606A>G	p.Lys536Glu	missense_variant	2/2	ENST00000303545.4
RNF139	XM_047421310.1	c.1225A>G	p.Lys409Glu	missense_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RNF139	ENST00000303545.4	c.1606A>G	p.Lys536Glu	missense_variant	2/2	1	NM_007218.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250840 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135558

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

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

Mar 16, 2022

The c.1606A>G (p.K536E) 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 1606, causing the lysine (K) at amino acid position 536 to be replaced by a glutamic acid (E). 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	0.12
BayesDel_addAF	Benign	-0.098	T
BayesDel_noAF	Benign	-0.30
Cadd	Benign	22
Dann	Uncertain	0.99
DEOGEN2	Benign	0.024	T
Eigen	Benign	-0.061
Eigen_PC	Benign	0.14
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-0.80	T
MutationAssessor	Benign	0.61	N
MutationTaster	Benign	0.96	D
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-0.39	N
REVEL	Benign	0.085
Sift	Benign	0.092	T
Sift4G	Benign	0.55	T
Polyphen		0.048	B
Vest4		0.38
MutPred		0.32		Loss of ubiquitination at K536 (P = 0.0134);
MVP		0.82
MPC		0.74
ClinPred		0.11	T
GERP RS		5.5
Varity_R		0.12
gMVP		0.69

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

LitVar

Other links and lift over

dbSNP: rs764209532; hg19: chr8-125499496;