6-127287133-C-A

Position:

• chr6-127287133-C-A

Variant summary

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

The NM_001242850.2(RNF146):​c.520C>A​(p.Pro174Thr) 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: RNF146 NM_001242850.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.66

Genes affected

RNF146 (HGNC:21336): (ring finger protein 146) Enables poly-ADP-D-ribose binding activity and ubiquitin-protein transferase activity. Involved in positive regulation of canonical Wnt signaling pathway; protein ubiquitination; and ubiquitin-dependent protein catabolic process. Located in cytosol; nucleoplasm; and plasma 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, 0.777

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RNF146	NM_001242850.2	c.520C>A	p.Pro174Thr	missense_variant	3/3	ENST00000368314.6	NP_001229779.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RNF146	ENST00000368314.6	c.520C>A	p.Pro174Thr	missense_variant	3/3	2	NM_001242850.2	ENSP00000357297	A1
RNF146	ENST00000610153.1	c.520C>A	p.Pro174Thr	missense_variant	3/3	2		ENSP00000476814	A1
RNF146	ENST00000608991.5	c.517C>A	p.Pro173Thr	missense_variant	5/5	4		ENSP00000477168	P4
RNF146	ENST00000356799.6	c.*525C>A		3_prime_UTR_variant	4/4	2		ENSP00000349253

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

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

Sep 22, 2022

The c.520C>A (p.P174T) alteration is located in exon 3 (coding exon 2) of the RNF146 gene. This alteration results from a C to A substitution at nucleotide position 520, causing the proline (P) at amino acid position 174 to be replaced by a threonine (T). 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	0.91
BayesDel_addAF	Uncertain	0.057	T
BayesDel_noAF	Benign	-0.16
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.13	T;T;.;T;.
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	.;D;D;.;.
M_CAP	Benign	0.022	T
MetaRNN	Pathogenic	0.78	D;D;D;D;D
MetaSVM	Benign	-0.96	T
MutationAssessor	Uncertain	2.2	M;M;.;M;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-6.7	D;.;D;.;.
REVEL	Uncertain	0.36
Sift	Uncertain	0.024	D;.;D;.;.
Sift4G	Uncertain	0.060	.;.;T;.;T
Polyphen		1.0	D;D;.;D;.
Vest4		0.81
MutPred		0.49		Loss of stability (P = 0.0437);Loss of stability (P = 0.0437);.;Loss of stability (P = 0.0437);.;
MVP		0.60
MPC		1.4
ClinPred		0.97	D
GERP RS		5.8
Varity_R		0.83
gMVP		0.74

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: chr6-127608278;