11-63719763-G-A

Variant names:

• chr11-63719763-G-A
• rs2011621484
• NM_001265589.2:c.1261G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001265589.2(RTN3):​c.1261G>A​(p.Val421Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. V421L) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RTN3 NM_001265589.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.91
• Publications: 0 publications found

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]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.043440282).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001265589.2. 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
	RTN3	NM_001265589.2	MANE Select	c.1261G>A	p.Val421Ile	missense	Exon 3 of 9	NP_001252518.1	O95197-1
	RTN3	NM_201428.3		c.1204G>A	p.Val402Ile	missense	Exon 2 of 8	NP_958831.1	O95197-2
	RTN3	NM_001265590.2		c.925G>A	p.Val309Ile	missense	Exon 2 of 8	NP_001252519.1	O95197-7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RTN3	ENST00000377819.10	TSL:1 MANE Select	c.1261G>A	p.Val421Ile	missense	Exon 3 of 9	ENSP00000367050.5	O95197-1
	RTN3	ENST00000339997.8	TSL:1	c.1204G>A	p.Val402Ile	missense	Exon 2 of 8	ENSP00000344106.4	O95197-2
	RTN3	ENST00000540798.5	TSL:1	c.925G>A	p.Val309Ile	missense	Exon 2 of 8	ENSP00000442733.1	O95197-7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	0.0020
DANN	Benign	0.47
DEOGEN2	Benign	0.010	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.022	N
LIST_S2	Benign	0.34	T
M_CAP	Benign	0.0046	T
MetaRNN	Benign	0.043	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.26	N
PhyloP100		-1.9
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.24	N
REVEL	Benign	0.017
Sift	Benign	0.52	T
Sift4G	Benign	0.40	T
Polyphen		0.0	B
Vest4		0.035
MutPred		0.067		Loss of glycosylation at T417 (P = 0.2302)
MVP		0.17
MPC		0.051
ClinPred		0.16	T
GERP RS		-7.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.2
Varity_R		0.028
gMVP		0.015
Mutation Taster		=99/1	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: rs2011621484; hg19: chr11-63487235;