2-86604087-T-C

Variant names:

• chr2-86604087-T-C
• rs1219956508
• NM_005667.4:c.1814A>G

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4 BS2

The NM_005667.4(RNF103):​c.1814A>G​(p.Glu605Gly) variant causes a missense change. The variant allele was found at a frequency of 0.0000164 in 1,461,518 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E605D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: RNF103 NM_005667.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.14
• Publications: 0 publications found

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:38847): (RNF103-CHMP3 readthrough) This locus represents naturally occurring read-through transcription between the neighboring RNF103 (ring finger protein 103) and CHMP3 (charged multivesicular body protein 3) genes. The read-through transcript encodes a fusion protein that shares sequence identity with each individual gene product. [provided by RefSeq, Oct 2011]

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

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.28525442).
• BS2: High AC in GnomAdExome4 at 24 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005667.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RNF103	NM_005667.4	MANE Select	c.1814A>G	p.Glu605Gly	missense	Exon 4 of 4	NP_005658.1	O00237
	RNF103	NM_001198951.1		c.1802A>G	p.Glu601Gly	missense	Exon 5 of 5	NP_001185880.1	O00237
	RNF103-CHMP3	NM_001198954.1		c.132+16243A>G		intron	N/A	NP_001185883.1	Q9Y3E7-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RNF103	ENST00000237455.5	TSL:1 MANE Select	c.1814A>G	p.Glu605Gly	missense	Exon 4 of 4	ENSP00000237455.4	O00237
	RNF103-CHMP3	ENST00000604011.5	TSL:2	c.132+16243A>G		intron	N/A	ENSP00000474823.1
	CHMP3-AS1	ENST00000426549.1	TSL:1	n.81T>C		non_coding_transcript_exon	Exon 1 of 2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000796 AC: 2 AN: 251182 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000164 AC: 24 AN: 1461518 Hom.: 0 Cov.: 31 AF XY: 0.00000825 AC XY: 6 AN XY: 727076

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.0000224 AC: 1 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53056

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000198 AC: 22 AN: 1112008

Other (OTH) AF: 0.00 AC: 0 AN: 60388

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000626 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.033	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.060	T
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.29	T
MetaSVM	Benign	-0.71	T
MutationAssessor	Benign	1.8	L
PhyloP100		7.1
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.96	N
REVEL	Benign	0.25
Sift	Benign	0.049	D
Sift4G	Uncertain	0.056	T
Polyphen		0.99	D
Vest4		0.32
MutPred		0.38		Loss of stability (P = 0.0895)
MVP		0.15
MPC		0.30
ClinPred		0.36	T
GERP RS		5.5
Varity_R		0.096
gMVP		0.41
Mutation Taster		=75/25	polymorphism

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

Other links and lift over

dbSNP: rs1219956508; hg19: chr2-86831210;