6-127287653-C-A

Position:

• chr6-127287653-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001242850.2(RNF146):​c.1040C>A​(p.Ser347Tyr) 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. 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: 5.75

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.34916162).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RNF146	NM_001242850.2	c.1040C>A	p.Ser347Tyr	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.1040C>A	p.Ser347Tyr	missense_variant	3/3	2	NM_001242850.2	ENSP00000357297	A1
RNF146	ENST00000610153.1	c.1040C>A	p.Ser347Tyr	missense_variant	3/3	2		ENSP00000476814	A1
RNF146	ENST00000608991.5	c.1037C>A	p.Ser346Tyr	missense_variant	5/5	4		ENSP00000477168	P4
RNF146	ENST00000356799.6	c.*1045C>A		3_prime_UTR_variant	4/4	2		ENSP00000349253

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

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

Apr 07, 2022

The c.1040C>A (p.S347Y) 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 1040, causing the serine (S) at amino acid position 347 to be replaced by a tyrosine (Y). 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	Uncertain	0.36
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.037	T;T;.;T;.
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.93	.;D;D;.;.
M_CAP	Benign	0.049	D
MetaRNN	Benign	0.35	T;T;T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Uncertain	2.1	M;M;.;M;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-1.4	N;.;N;.;.
REVEL	Benign	0.23
Sift	Pathogenic	0.0	D;.;D;.;.
Sift4G	Pathogenic	0.0	.;.;D;.;D
Polyphen		1.0	D;D;.;D;.
Vest4		0.41
MutPred		0.34		Gain of sheet (P = 0.0221);Gain of sheet (P = 0.0221);.;Gain of sheet (P = 0.0221);.;
MVP		0.53
MPC		1.4
ClinPred		0.89	D
GERP RS		5.8
Varity_R		0.52
gMVP		0.55

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: chr6-127608798;