2-86604177-G-A

Variant summary

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

The NM_005667.4(RNF103):​c.1724C>T​(p.Ala575Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,414 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

RNF103
NM_005667.4 missense

Scores

1
2
16

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.87
Variant links:
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]
CHMP3-AS1 (HGNC:55795): (CHMP3 and RNF103 antisense RNA 1)

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
RNF103NM_005667.4 linkuse as main transcriptc.1724C>T p.Ala575Val missense_variant 4/4 ENST00000237455.5 NP_005658.1
RNF103-CHMP3NM_001198954.1 linkuse as main transcriptc.132+16153C>T intron_variant NP_001185883.1
CHMP3-AS1NR_183900.1 linkuse as main transcriptn.254-12999G>A intron_variant, non_coding_transcript_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
RNF103ENST00000237455.5 linkuse as main transcriptc.1724C>T p.Ala575Val missense_variant 4/41 NM_005667.4 ENSP00000237455 P1
CHMP3-AS1ENST00000439077.1 linkuse as main transcriptn.249-12999G>A intron_variant, non_coding_transcript_variant 3

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.00000205
AC:
3
AN:
1461414
Hom.:
0
Cov.:
31
AF XY:
0.00000275
AC XY:
2
AN XY:
727034
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000232
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
8.99e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
Asia WGS
AF:
0.00144
AC:
5
AN:
3478

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsAug 15, 2023The c.1724C>T (p.A575V) alteration is located in exon 4 (coding exon 4) of the RNF103 gene. This alteration results from a C to T substitution at nucleotide position 1724, causing the alanine (A) at amino acid position 575 to be replaced by a valine (V). 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
0.074
BayesDel_addAF
Benign
-0.077
T
BayesDel_noAF
Benign
-0.35
CADD
Benign
20
DANN
Uncertain
0.99
DEOGEN2
Benign
0.043
T
Eigen
Benign
-0.064
Eigen_PC
Benign
0.13
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Uncertain
0.89
D
M_CAP
Benign
0.0098
T
MetaRNN
Benign
0.15
T
MetaSVM
Benign
-0.95
T
MutationAssessor
Benign
1.6
L
MutationTaster
Benign
1.0
D;D
PrimateAI
Benign
0.28
T
PROVEAN
Benign
-0.52
N
REVEL
Benign
0.11
Sift
Benign
0.053
T
Sift4G
Benign
0.089
T
Polyphen
0.049
B
Vest4
0.17
MutPred
0.24
Loss of loop (P = 0.0804);
MVP
0.29
MPC
0.20
ClinPred
0.26
T
GERP RS
5.5
Varity_R
0.11
gMVP
0.30

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.27
Details are displayed if max score is > 0.2
DS_DG_spliceai
0.27
Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs372592911; hg19: chr2-86831300; API