11-63719346-G-A

Position:

• chr11-63719346-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001265589.2(RTN3):​c.844G>A​(p.Glu282Lys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: RTN3 NM_001265589.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.85

Genes affected

RTN3 (HGNC:10469): (reticulon 3) This gene belongs to the reticulon family of highly conserved genes that are preferentially expressed in neuroendocrine tissues. This family of proteins interact with, and modulate the activity of beta-amyloid converting enzyme 1 (BACE1), and the production of amyloid-beta. An increase in the expression of any reticulon protein substantially reduces the production of amyloid-beta, suggesting that reticulon proteins are negative modulators of BACE1 in cells. Alternatively spliced transcript variants encoding different isoforms have been found for this gene, and pseudogenes of this gene are located on chromosomes 4 and 12. [provided by RefSeq, May 2012]

RTN3 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.41371277).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RTN3	NM_001265589.2	c.844G>A	p.Glu282Lys	missense_variant	3/9	ENST00000377819.10	NP_001252518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RTN3	ENST00000377819.10	c.844G>A	p.Glu282Lys	missense_variant	3/9	1	NM_001265589.2	ENSP00000367050.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

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

Nov 10, 2022

The c.787G>A (p.E263K) alteration is located in exon 2 (coding exon 2) of the RTN3 gene. This alteration results from a G to A substitution at nucleotide position 787, causing the glutamic acid (E) at amino acid position 263 to be replaced by a lysine (K). 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	0.11
BayesDel_addAF	Benign	-0.070	T
BayesDel_noAF	Benign	-0.34
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.070	T;.;.
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.85	T;T;T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.41	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	L;.;.
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-1.2	N;N;N
REVEL	Benign	0.20
Sift	Pathogenic	0.0	D;D;D
Sift4G	Uncertain	0.028	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.54
MutPred		0.15		Gain of ubiquitination at E282 (P = 0.0016);.;.;
MVP		0.40
MPC		0.39
ClinPred		0.92	D
GERP RS		6.0
Varity_R		0.28
gMVP		0.11

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: chr11-63486818;