6-106572103-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The NM_032730.5(RTN4IP1):c.1084A>T(p.Ile362Phe) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,459,290 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. I362I) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: RTN4IP1 NM_032730.5 missense, splice_region
• Scores: Splicing: ADA: 0.9425
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 2.22

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
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. Scorers claiming Benign: dbscSNV1_ADA.
• PP5: Variant 6-106572103-T-A is Pathogenic according to our data. Variant chr6-106572103-T-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 985722.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RTN4IP1	NM_032730.5	c.1084A>T	p.Ile362Phe	missense_variant, splice_region_variant	9/9	ENST00000369063.8
RTN4IP1	NM_001318746.1	c.784A>T	p.Ile262Phe	missense_variant, splice_region_variant	9/9
RTN4IP1	XM_011536192.3	c.844A>T	p.Ile282Phe	missense_variant, splice_region_variant	10/10
RTN4IP1	XM_017011376.3	c.*33A>T		splice_region_variant, 3_prime_UTR_variant	8/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RTN4IP1	ENST00000369063.8	c.1084A>T	p.Ile362Phe	missense_variant, splice_region_variant	9/9	1	NM_032730.5	P1
RTN4IP1	ENST00000539449.2	c.*33A>T		splice_region_variant, 3_prime_UTR_variant	6/6	2
RTN4IP1	ENST00000493619.1	n.82A>T		splice_region_variant, non_coding_transcript_exon_variant	2/2	3
RTN4IP1	ENST00000498091.1	n.305A>T		splice_region_variant, non_coding_transcript_exon_variant	2/2	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1459290 Hom.: 0 Cov.: 29 AF XY: 0.00000275 AC XY: 2 AN XY: 726114

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: 0.00000270

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Inborn genetic diseases Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 22, 2019

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jul 05, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 985722). This missense change has been observed in individual(s) with optic atrophy (PMID: 29181510, 33841295). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces isoleucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 362 of the RTN4IP1 protein (p.Ile362Phe). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.69
BayesDel_addAF	Uncertain	0.037	T
BayesDel_noAF	Benign	-0.18
Cadd	Pathogenic	27
Dann	Uncertain	0.99
DEOGEN2	Benign	0.21	T
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.045	D
MetaRNN	Pathogenic	0.80	D
MetaSVM	Benign	-0.85	T
MutationAssessor	Uncertain	2.7	M
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.48	T
PROVEAN	Uncertain	-3.5	D
REVEL	Benign	0.25
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0030	D
Polyphen		0.94	P
Vest4		0.71
MutPred		0.67		Loss of catalytic residue at P364 (P = 0.0271);
MVP		0.45
MPC		0.74
ClinPred		0.99	D
GERP RS		4.9
Varity_R		0.72
gMVP		0.92

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.94
dbscSNV1_RF	Pathogenic	0.85
SpliceAI score (max)		0.51		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.51		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1775080757; hg19: chr6-107019978;