chr11-57476775-G-A

Position:

• chr11-57476775-G-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The ENST00000335099.8(RTN4RL2):​c.1127G>A​(p.Gly376Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000523 in 1,337,220 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000052 (0 hom.)
• Consequence: RTN4RL2 ENST00000335099.8 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.825

Genes affected

RTN4RL2 (HGNC:23053): (reticulon 4 receptor like 2) Enables signaling receptor activity. Predicted to be involved in cell surface receptor signaling pathway; corpus callosum development; and negative regulation of neuron projection development. Located in cell surface. Is anchored component of plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000255301 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.10278422).
• BS2: High AC in GnomAdExome4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RTN4RL2	NM_178570.3	c.1127G>A	p.Gly376Asp	missense_variant	3/3	ENST00000335099.8	NP_848665.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RTN4RL2	ENST00000335099.8	c.1127G>A	p.Gly376Asp	missense_variant	3/3	1	NM_178570.3	ENSP00000335397.3
ENSG00000255301	ENST00000528885.1	n.539-137C>T		intron_variant		2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000523 AC: 7 AN: 1337220 Hom.: 0 Cov.: 32 AF XY: 0.00000608 AC XY: 4 AN XY: 658252

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: 0.00000661

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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

Aug 01, 2022

The c.1127G>A (p.G376D) alteration is located in exon 3 (coding exon 3) of the RTN4RL2 gene. This alteration results from a G to A substitution at nucleotide position 1127, causing the glycine (G) at amino acid position 376 to be replaced by an aspartic acid (D). 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	0.13
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.056	T
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.45
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.66	T
M_CAP	Pathogenic	0.33	D
MetaRNN	Benign	0.10	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	N
MutationTaster	Benign	1.0	N
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	0.030	N
REVEL	Benign	0.054
Sift	Benign	0.51	T
Sift4G	Benign	0.45	T
Polyphen		0.0	B
Vest4		0.23
MutPred		0.41		Loss of catalytic residue at Y374 (P = 0.1126);
MVP		0.55
MPC		1.4
ClinPred		0.095	T
GERP RS		2.1
Varity_R		0.071
gMVP		0.27

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: rs1943599499; hg19: chr11-57244248;