chr2-86605140-C-G

Position:

• chr2-86605140-C-G

Variant summary

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

The ENST00000237455.5(RNF103):​c.761G>C​(p.Ser254Thr) variant causes a missense change. 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: 32)
• Consequence: RNF103 ENST00000237455.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.94

Genes affected

RNF103 (HGNC:12859): (ring finger protein 103) The protein encoded by this gene contains a RING-H2 finger, a motif known to be involved in protein-protein and protein-DNA interactions. This gene is highly expressed in normal cerebellum, but not in the cerebral cortex. The expression of the rat counterpart in the frontal cortex and hippocampus was shown to be induced by elctroconvulsive treatment (ECT) as well as chronic antidepressant treatment, suggesting that this gene may be a molecular target for ECT and antidepressants. The protein is a ubiquitin ligase that functions in the endoplasmic reticulum-associated degradation pathway. Alternative splicing of this gene results in multiple transcript variants. Read-through transcription also exists between this gene and the downstream CHMP3 (charged multivesicular body protein 3) gene. [provided by RefSeq, Oct 2011]

RNF103-CHMP3 (HGNC:):

CHMP3-AS1 (HGNC:55795): (CHMP3 and RNF103 antisense RNA 1)

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, 0.782

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RNF103	NM_005667.4	c.761G>C	p.Ser254Thr	missense_variant	4/4	ENST00000237455.5	NP_005658.1
RNF103-CHMP3	NM_001198954.1	c.132+15190G>C		intron_variant			NP_001185883.1
CHMP3-AS1	NR_183900.1	n.254-12036C>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RNF103	ENST00000237455.5	c.761G>C	p.Ser254Thr	missense_variant	4/4	1	NM_005667.4	ENSP00000237455	P1
CHMP3-AS1	ENST00000439077.1	n.249-12036C>G		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

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 27, 2021

The c.761G>C (p.S254T) alteration is located in exon 4 (coding exon 4) of the RNF103 gene. This alteration results from a G to C substitution at nucleotide position 761, causing the serine (S) at amino acid position 254 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	Uncertain	0.56
BayesDel_addAF	Uncertain	0.013	T
BayesDel_noAF	Benign	-0.22
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.27	T
Eigen	Pathogenic	0.70
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.056	D
MetaRNN	Pathogenic	0.78	D
MetaSVM	Benign	-0.38	T
MutationAssessor	Benign	2.0	M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.21
Sift	Uncertain	0.0080	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.99	D
Vest4		0.81
MutPred		0.33		Loss of sheet (P = 0.0817);
MVP		0.50
MPC		0.73
ClinPred		0.91	D
GERP RS		5.1
Varity_R		0.39
gMVP		0.92

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: chr2-86832263;