rs17857046

Variant names:

• chr2-86605150-A-G
• rs17857046
• NM_005667.4:c.751T>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_005667.4(RNF103):​c.751T>C​(p.Ser251Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RNF103 NM_005667.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.94
• Publications: 1 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: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.847

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RNF103	NM_005667.4	MANE Select	c.751T>C	p.Ser251Pro	missense	Exon 4 of 4	NP_005658.1
	RNF103	NM_001198951.1		c.739T>C	p.Ser247Pro	missense	Exon 5 of 5	NP_001185880.1
	RNF103-CHMP3	NM_001198954.1		c.132+15180T>C		intron	N/A	NP_001185883.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RNF103	ENST00000237455.5	TSL:1 MANE Select	c.751T>C	p.Ser251Pro	missense	Exon 4 of 4	ENSP00000237455.4
	RNF103-CHMP3	ENST00000604011.5	TSL:2	c.132+15180T>C		intron	N/A	ENSP00000474823.1
	CHMP3-AS1	ENST00000426549.1	TSL:1	n.357+787A>G		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.24
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.31	T
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D
M_CAP	Uncertain	0.20	D
MetaRNN	Pathogenic	0.85	D
MetaSVM	Uncertain	-0.18	T
MutationAssessor	Benign	2.0	M
PhyloP100		8.9
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-2.0	N
REVEL	Uncertain	0.53
Sift	Uncertain	0.0020	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.93
MutPred		0.42		Gain of loop (P = 0.0166)
MVP		0.73
MPC		0.88
ClinPred		0.93	D
GERP RS		5.1
Varity_R		0.67
gMVP		0.96
Mutation Taster		=35/65	disease causing

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: rs17857046; hg19: chr2-86832273;