chr22-20242201-A-G

Position:

• chr22-20242201-A-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_023004.6(RTN4R):​c.932T>C​(p.Val311Ala) 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. 15/21 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)
• Consequence: RTN4R NM_023004.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.103

Genes affected

RTN4R (HGNC:18601): (reticulon 4 receptor) This gene encodes the receptor for reticulon 4, oligodendrocyte myelin glycoprotein and myelin-associated glycoprotein. This receptor mediates axonal growth inhibition and may play a role in regulating axonal regeneration and plasticity in the adult central nervous system. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.062441915).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RTN4R	NM_023004.6	c.932T>C	p.Val311Ala	missense_variant	2/2	ENST00000043402.8	NP_075380.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RTN4R	ENST00000043402.8	c.932T>C	p.Val311Ala	missense_variant	2/2	1	NM_023004.6	ENSP00000043402	P1
RTN4R	ENST00000425986.1	c.1190T>C	p.Val397Ala	missense_variant	2/2	2		ENSP00000403535
RTN4R	ENST00000416372.5	c.992T>C	p.Val331Ala	missense_variant	2/2	3		ENSP00000396872

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000825 AC: 1

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

Jan 04, 2022

The c.932T>C (p.V311A) alteration is located in exon 2 (coding exon 2) of the RTN4R gene. This alteration results from a T to C substitution at nucleotide position 932, causing the valine (V) at amino acid position 311 to be replaced by an alanine (A). 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	0.057
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	0.86
DANN	Benign	0.68
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.85
Eigen_PC	Benign	-0.99
FATHMM_MKL	Benign	0.021	N
LIST_S2	Benign	0.56	T
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.062	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	N
MutationTaster	Benign	1.0	N
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	0.060	N
REVEL	Benign	0.061
Sift	Benign	0.66	T
Sift4G	Benign	0.33	T
Polyphen		0.0	B
Vest4		0.13
MutPred		0.57		Gain of disorder (P = 0.0434);
MVP		0.64
MPC		0.45
ClinPred		0.022	T
GERP RS		-2.9
Varity_R		0.050
gMVP		0.51

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: rs762415688; hg19: chr22-20229724;