17-1936654-A-T

Position:

• chr17-1936654-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The ENST00000331238.7(RTN4RL1):​c.1168T>A​(p.Phe390Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000000695 in 1,439,002 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: RTN4RL1 ENST00000331238.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.27

Genes affected

RTN4RL1 (HGNC:21329): (reticulon 4 receptor like 1) Enables signaling receptor activity. Predicted to be involved in negative regulation of axon regeneration. Located in cell surface. Is anchored component of plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.24927795).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RTN4RL1	NM_178568.4	c.1168T>A	p.Phe390Ile	missense_variant	2/2	ENST00000331238.7	NP_848663.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RTN4RL1	ENST00000331238.7	c.1168T>A	p.Phe390Ile	missense_variant	2/2	1	NM_178568.4	ENSP00000330631	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.95e-7 AC: 1 AN: 1439002 Hom.: 0 Cov.: 71 AF XY: 0.00 AC XY: 0 AN XY: 714510

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.08e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

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

Oct 05, 2022

The c.1168T>A (p.F390I) alteration is located in exon 2 (coding exon 2) of the RTN4RL1 gene. This alteration results from a T to A substitution at nucleotide position 1168, causing the phenylalanine (F) at amino acid position 390 to be replaced by an isoleucine (I). 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	0.28
BayesDel_addAF	Benign	-0.084	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	19
DANN	Benign	0.97
DEOGEN2	Benign	0.088	T
Eigen	Benign	0.051
Eigen_PC	Benign	0.15
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.73	T
M_CAP	Benign	0.031	D
MetaRNN	Benign	0.25	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	1.9	L
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.090
Sift	Benign	0.12	T
Sift4G	Benign	0.39	T
Polyphen		0.71	P
Vest4		0.50
MutPred		0.25		Gain of glycosylation at S389 (P = 0.0837);
MVP		0.30
MPC		0.97
ClinPred		0.60	D
GERP RS		5.3
Varity_R		0.13
gMVP		0.29

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

LitVar

Other links and lift over

dbSNP: rs981499143; hg19: chr17-1839948;