rs140586853

Variant names:

• chr6-106572093-A-G
• rs140586853
• NM_032730.5:c.1094T>C

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. 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:3
• Conservation: PhyloP100: 6.42
• Publications: 0 publications found

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]

CRYBG1 (HGNC:356): (crystallin beta-gamma domain containing 1) Predicted to enable carbohydrate binding activity. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• 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 VariationId 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032730.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RTN4IP1	NM_032730.5	MANE Select	c.1094T>C	p.Val365Ala	missense	Exon 9 of 9	NP_116119.2	Q8WWV3-1
	RTN4IP1	NM_001318746.1		c.794T>C	p.Val265Ala	missense	Exon 9 of 9	NP_001305675.1	Q8WWV3-2
	CRYBG1	NM_001371242.2	MANE Select	c.*3527A>G		downstream_gene	N/A	NP_001358171.1	Q9Y4K1-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RTN4IP1	ENST00000369063.8	TSL:1 MANE Select	c.1094T>C	p.Val365Ala	missense	Exon 9 of 9	ENSP00000358059.3	Q8WWV3-1
	RTN4IP1	ENST00000865782.1		c.1112T>C	p.Val371Ala	missense	Exon 9 of 9	ENSP00000535841.1
	RTN4IP1	ENST00000947236.1		c.1076T>C	p.Val359Ala	missense	Exon 9 of 9	ENSP00000617295.1

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

GnomAD2 exomes AF: 0.000271 AC: 68 AN: 250764 AF XY: 0.000140

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 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

African (AFR) AF: 0.00448 AC: 150 AN: 33466

American (AMR) AF: 0.0000895 AC: 4 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86242

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53390

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000720 AC: 8 AN: 1111548

Other (OTH) AF: 0.000232 AC: 14 AN: 60376

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

African (AFR) AF: 0.00411 AC: 171 AN: 41582

American (AMR) AF: 0.000131 AC: 2 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.000472 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

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	RTN4IP1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		6.4
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
Mutation Taster		=66/34	polymorphism

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

Other links and lift over

dbSNP: rs140586853; hg19: chr6-107019968;