NM_001265589.2:c.64C>T

Variant names:

• chr11-63681700-C-T
• NM_001265589.2:c.64C>T

Variant summary

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

The NM_001265589.2(RTN3):​c.64C>T​(p.Pro22Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,458,540 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: RTN3 NM_001265589.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.235
• 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: 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=0.09170136).

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.64C>T	p.Pro22Ser	missense	Exon 1 of 9	NP_001252518.1	O95197-1
	RTN3	NM_201428.3		c.64C>T	p.Pro22Ser	missense	Exon 1 of 8	NP_958831.1	O95197-2
	RTN3	NM_001265590.2		c.64C>T	p.Pro22Ser	missense	Exon 1 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.64C>T	p.Pro22Ser	missense	Exon 1 of 9	ENSP00000367050.5	O95197-1
	RTN3	ENST00000339997.8	TSL:1	c.64C>T	p.Pro22Ser	missense	Exon 1 of 8	ENSP00000344106.4	O95197-2
	RTN3	ENST00000540798.5	TSL:1	c.64C>T	p.Pro22Ser	missense	Exon 1 of 8	ENSP00000442733.1	O95197-7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1458540 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 725484

African (AFR) AF: 0.00 AC: 0 AN: 33316

American (AMR) AF: 0.00 AC: 0 AN: 44524

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26014

East Asian (EAS) AF: 0.00 AC: 0 AN: 39592

South Asian (SAS) AF: 0.00 AC: 0 AN: 86054

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52306

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5752

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1110720

Other (OTH) AF: 0.00 AC: 0 AN: 60262

GnomAD4 genome Cov.: 32

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	0.079
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	19
DANN	Benign	0.97
DEOGEN2	Benign	0.020	T
Eigen	Benign	-0.46
Eigen_PC	Benign	-0.34
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.75	T
M_CAP	Uncertain	0.28	D
MetaRNN	Benign	0.092	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.97	L
PhyloP100		0.23
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-0.37	N
REVEL	Benign	0.023
Sift	Benign	0.27	T
Sift4G	Benign	0.11	T
Polyphen		0.0	B
Vest4		0.092
MutPred		0.16		Gain of phosphorylation at P22 (P = 0.0056)
MVP		0.50
MPC		0.059
ClinPred		0.37	T
GERP RS		2.3
PromoterAI		0.022	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.046
gMVP		0.22
Mutation Taster		=77/23	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

hg19: chr11-63449172;