2-86604563-T-G

Variant names:

• chr2-86604563-T-G
• rs752946051
• NM_005667.4:c.1338A>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005667.4(RNF103):​c.1338A>C​(p.Glu446Asp) 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 1,461,880 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: RNF103 NM_005667.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.24
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13936895).

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.1338A>C	p.Glu446Asp	missense	Exon 4 of 4	NP_005658.1	O00237
	RNF103	NM_001198951.1		c.1326A>C	p.Glu442Asp	missense	Exon 5 of 5	NP_001185880.1	O00237
	RNF103-CHMP3	NM_001198954.1		c.132+15767A>C		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.1338A>C	p.Glu446Asp	missense	Exon 4 of 4	ENSP00000237455.4	O00237
	RNF103-CHMP3	ENST00000604011.5	TSL:2	c.132+15767A>C		intron	N/A	ENSP00000474823.1
	CHMP3-AS1	ENST00000426549.1	TSL:1	n.357+200T>G		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251308 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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461880 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727236

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112008

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	19
DANN	Benign	0.95
DEOGEN2	Benign	0.073	T
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.27
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.14	N
PhyloP100		1.2
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	0.0	N
REVEL	Benign	0.14
Sift	Benign	0.37	T
Sift4G	Benign	0.46	T
Polyphen		0.99	D
Vest4		0.11
MutPred		0.14		Loss of helix (P = 0.028)
MVP		0.38
MPC		0.74
ClinPred		0.35	T
GERP RS		-1.4
Varity_R		0.063
gMVP		0.53
Mutation Taster		=89/11	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: rs752946051; hg19: chr2-86831686;