12-116750283-A-G

Position:

• chr12-116750283-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001382266.1(RNFT2):​c.526A>G​(p.Lys176Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: RNFT2 NM_001382266.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.91

Genes affected

RNFT2 (HGNC:25905): (ring finger protein, transmembrane 2) Predicted to enable ubiquitin protein ligase activity. Predicted to be involved in positive regulation of ERAD pathway and protein ubiquitination. Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.816

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RNFT2	NM_001382266.1	c.526A>G	p.Lys176Glu	missense_variant	4/11	ENST00000257575.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RNFT2	ENST00000257575.9	c.526A>G	p.Lys176Glu	missense_variant	4/11	5	NM_001382266.1	P1
RNFT2	ENST00000392549.7	c.526A>G	p.Lys176Glu	missense_variant	4/12	5		P1
RNFT2	ENST00000407967.7	c.526A>G	p.Lys176Glu	missense_variant	4/11	5
RNFT2	ENST00000547718.5	c.*483A>G		3_prime_UTR_variant, NMD_transcript_variant	5/12	2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 31

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 16, 2021

The c.526A>G (p.K176E) alteration is located in exon 4 (coding exon 3) of the RNFT2 gene. This alteration results from a A to G substitution at nucleotide position 526, causing the lysine (K) at amino acid position 176 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	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.24
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.47	T;T;.;T;T
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Benign	0.040	D
MetaRNN	Pathogenic	0.82	D;D;D;D;D
MetaSVM	Benign	-0.44	T
MutationAssessor	Pathogenic	3.1	M;M;M;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-3.3	D;D;D;.;D
REVEL	Uncertain	0.58
Sift	Uncertain	0.0020	D;D;D;.;D
Sift4G	Uncertain	0.015	D;D;D;D;D
Polyphen		0.99	D;D;.;.;.
Vest4		0.94
MutPred		0.48		Loss of ubiquitination at K176 (P = 0.0233);Loss of ubiquitination at K176 (P = 0.0233);Loss of ubiquitination at K176 (P = 0.0233);.;Loss of ubiquitination at K176 (P = 0.0233);
MVP		0.20
MPC		1.0
ClinPred		0.98	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.77
gMVP		0.93

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: chr12-117188088;