6-127287305-G-C

Position:

• chr6-127287305-G-C

Variant summary

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

The NM_001242850.2(RNF146):​c.692G>C​(p.Ser231Thr) 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. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: RNF146 NM_001242850.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.79

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2483542).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RNF146	NM_001242850.2	c.692G>C	p.Ser231Thr	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.692G>C	p.Ser231Thr	missense_variant	3/3	2	NM_001242850.2	ENSP00000357297	A1
RNF146	ENST00000610153.1	c.692G>C	p.Ser231Thr	missense_variant	3/3	2		ENSP00000476814	A1
RNF146	ENST00000608991.5	c.689G>C	p.Ser230Thr	missense_variant	5/5	4		ENSP00000477168	P4
RNF146	ENST00000356799.6	c.*697G>C		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

Mar 01, 2024

The c.692G>C (p.S231T) alteration is located in exon 3 (coding exon 2) of the RNF146 gene. This alteration results from a G to C substitution at nucleotide position 692, causing the serine (S) at amino acid position 231 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	Benign	0.076
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	23
DANN	Benign	0.96
DEOGEN2	Benign	0.023	T;T;.;T;.
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.69	.;T;T;.;.
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.25	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.5	L;L;.;L;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-0.68	N;.;N;.;.
REVEL	Benign	0.17
Sift	Uncertain	0.0050	D;.;D;.;.
Sift4G	Benign	0.22	.;.;T;.;T
Polyphen		0.90	P;P;.;P;.
Vest4		0.27
MutPred		0.092		Gain of glycosylation at T230 (P = 0.0829);Gain of glycosylation at T230 (P = 0.0829);.;Gain of glycosylation at T230 (P = 0.0829);.;
MVP		0.36
MPC		0.49
ClinPred		0.79	D
GERP RS		6.0
Varity_R		0.25
gMVP		0.39

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: chr6-127608450;