chr22-20241832-G-T

Position:

• chr22-20241832-G-T

Variant summary

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

The NM_023004.6(RTN4R):​c.1301C>A​(p.Ala434Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000689 in 1,451,274 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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: RTN4R NM_023004.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.715

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 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=0.26298302).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RTN4R	NM_023004.6	c.1301C>A	p.Ala434Glu	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.1301C>A	p.Ala434Glu	missense_variant	2/2	1	NM_023004.6	ENSP00000043402	P1
RTN4R	ENST00000425986.1	c.1559C>A	p.Ala520Glu	missense_variant	2/2	2		ENSP00000403535
RTN4R	ENST00000416372.5	c.1361C>A	p.Ala454Glu	missense_variant	2/2	3		ENSP00000396872

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.89e-7 AC: 1 AN: 1451274 Hom.: 0 Cov.: 31 AF XY: 0.00000139 AC XY: 1 AN XY: 721420

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: 9.03e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

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

Dec 19, 2022

The c.1301C>A (p.A434E) alteration is located in exon 2 (coding exon 2) of the RTN4R gene. This alteration results from a C to A substitution at nucleotide position 1301, causing the alanine (A) at amino acid position 434 to be replaced by a glutamic acid (E). 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	0.15
BayesDel_addAF	Benign	-0.011	T
BayesDel_noAF	Benign	-0.25
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.22	T
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.38
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.71	T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.26	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.1	M
MutationTaster	Benign	0.98	N
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.22
Sift	Uncertain	0.0060	D
Sift4G	Benign	0.063	T
Polyphen		0.99	D
Vest4		0.35
MutPred		0.33		Gain of solvent accessibility (P = 0.0145);
MVP		0.51
MPC		0.74
ClinPred		0.61	D
GERP RS		2.3
Varity_R		0.21
gMVP		0.28

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr22-20229355;