rs372054380

chr6-106622936-C-Gchr6-106622936-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PM5 PP3

The NM_032730.5(RTN4IP1):c.308G>C(p.Arg103Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,172 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R103C) has been classified as Uncertain significance.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: RTN4IP1 NM_032730.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.54

Genes affected

RTN4IP1 (HGNC:18647): (reticulon 4 interacting protein 1) This gene encodes a mitochondrial protein that interacts with reticulon 4, which is a potent inhibitor of regeneration following spinal cord injury. This interaction may be important for reticulon-induced inhibition of neurite growth. Mutations in this gene can cause optic atrophy 10, with or without ataxia, cognitive disability, and seizures. There is a pseudogene for this gene on chromosome 12. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2016]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr6-106622936-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 218932.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.793

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RTN4IP1	NM_032730.5	c.308G>C	p.Arg103Pro	missense_variant	2/9	ENST00000369063.8
RTN4IP1	NM_001318746.1	c.8G>C	p.Arg3Pro	missense_variant	2/9
RTN4IP1	XM_011536192.3	c.68G>C	p.Arg23Pro	missense_variant	3/10
RTN4IP1	XM_017011376.3	c.308G>C	p.Arg103Pro	missense_variant	2/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RTN4IP1	ENST00000369063.8	c.308G>C	p.Arg103Pro	missense_variant	2/9	1	NM_032730.5	P1
RTN4IP1	ENST00000539449.2	c.308G>C	p.Arg103Pro	missense_variant	2/6	2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152172 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152172 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74338

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Uncertain	0.091	D
BayesDel_noAF	Benign	-0.11
Cadd	Pathogenic	28
Dann	Uncertain	1.0
DEOGEN2	Benign	0.12	T;T
Eigen	Pathogenic	0.69
Eigen_PC	Pathogenic	0.66
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.79	D;D
MetaSVM	Benign	-0.70	T
MutationAssessor	Benign	1.2	L;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.67	T
PROVEAN	Pathogenic	-5.2	D;D
REVEL	Uncertain	0.36
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.0050	D;D
Polyphen		1.0	D;D
Vest4		0.73
MutPred		0.53		Loss of solvent accessibility (P = 0.0079);Loss of solvent accessibility (P = 0.0079);
MVP		0.64
MPC		0.79
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.94
gMVP		0.87

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: rs372054380; hg19: chr6-107070811;