6-106572093-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PM2 BP4_Strong BP6_Very_Strong BS1

The NM_032730.5(RTN4IP1):c.1094T>C(p.Val365Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000217 in 1,613,666 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. V365V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00012 (1 hom.)
• Consequence: RTN4IP1 NM_032730.5 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 6.42

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 Benign. Variant got -14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.025182098).
• BP6: Variant 6-106572093-A-G is Benign according to our data. Variant chr6-106572093-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 704000.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00114 (174/152336) while in subpopulation AFR AF= 0.00411 (171/41582). AF 95% confidence interval is 0.00361. There are 0 homozygotes in gnomad4. There are 75 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RTN4IP1	NM_032730.5	c.1094T>C	p.Val365Ala	missense_variant	9/9	ENST00000369063.8
RTN4IP1	NM_001318746.1	c.794T>C	p.Val265Ala	missense_variant	9/9
RTN4IP1	XM_011536192.3	c.854T>C	p.Val285Ala	missense_variant	10/10
RTN4IP1	XM_017011376.3	c.*43T>C		3_prime_UTR_variant	8/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RTN4IP1	ENST00000369063.8	c.1094T>C	p.Val365Ala	missense_variant	9/9	1	NM_032730.5	P1
RTN4IP1	ENST00000539449.2	c.*43T>C		3_prime_UTR_variant	6/6	2
RTN4IP1	ENST00000493619.1	n.92T>C		non_coding_transcript_exon_variant	2/2	3
RTN4IP1	ENST00000498091.1	n.315T>C		non_coding_transcript_exon_variant	2/2	2

Frequencies

GnomAD3 genomes AF: 0.00114 AC: 174 AN: 152218 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00412

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000271 AC: 68 AN: 250764 Hom.: 0 AF XY: 0.000140 AC XY: 19 AN XY: 135626

Gnomad AFR exome AF: 0.00395

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000120 AC: 176 AN: 1461330 Hom.: 1 Cov.: 30 AF XY: 0.0000770 AC XY: 56 AN XY: 726990

Gnomad4 AFR exome AF: 0.00448

Gnomad4 AMR exome AF: 0.0000895

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: 0.00000720

Gnomad4 OTH exome AF: 0.000232

GnomAD4 genome AF: 0.00114 AC: 174 AN: 152336 Hom.: 0 Cov.: 32 AF XY: 0.00101 AC XY: 75 AN XY: 74490

Gnomad4 AFR AF: 0.00411

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000223 Hom.: 0

Bravo AF: 0.00132

ESP6500AA AF: 0.00340 AC: 15

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000354 AC: 43

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 07, 2023

- -

RTN4IP1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 27, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.46
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.090
Cadd	Pathogenic	26
Dann	Uncertain	1.0
DEOGEN2	Benign	0.20	T
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.025	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Uncertain	2.3	M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.54	T
PROVEAN	Uncertain	-2.9	D
REVEL	Uncertain	0.38
Sift	Uncertain	0.011	D
Sift4G	Uncertain	0.046	D
Polyphen		0.99	D
Vest4		0.73
MVP		0.47
MPC		0.67
ClinPred		0.068	T
GERP RS		6.0
Varity_R		0.41
gMVP		0.82

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: rs140586853; hg19: chr6-107019968;