6-106572099-C-G

Variant names:

• chr6-106572099-C-G
• rs372866009
• NM_032730.5:c.1088G>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_032730.5(RTN4IP1):​c.1088G>C​(p.Arg363Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,574 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign 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. R363Q) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: RTN4IP1 NM_032730.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0920
• 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.35264158).

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.1088G>C	p.Arg363Pro	missense	Exon 9 of 9	NP_116119.2	Q8WWV3-1
	RTN4IP1	NM_001318746.1		c.788G>C	p.Arg263Pro	missense	Exon 9 of 9	NP_001305675.1	Q8WWV3-2
	CRYBG1	NM_001371242.2	MANE Select	c.*3533C>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.1088G>C	p.Arg363Pro	missense	Exon 9 of 9	ENSP00000358059.3	Q8WWV3-1
	RTN4IP1	ENST00000865782.1		c.1106G>C	p.Arg369Pro	missense	Exon 9 of 9	ENSP00000535841.1
	RTN4IP1	ENST00000947236.1		c.1070G>C	p.Arg357Pro	missense	Exon 9 of 9	ENSP00000617295.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460574 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726660

African (AFR) AF: 0.00 AC: 0 AN: 33452

American (AMR) AF: 0.00 AC: 0 AN: 44682

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86166

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53382

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1110948

Other (OTH) AF: 0.00 AC: 0 AN: 60360

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.79
BayesDel_addAF	Benign	-0.085	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.20	T
Eigen	Benign	-0.13
Eigen_PC	Benign	-0.31
FATHMM_MKL	Benign	0.16	N
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.35	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Pathogenic	3.9	H
PhyloP100		-0.092
PrimateAI	Benign	0.21	T
PROVEAN	Uncertain	-2.7	D
REVEL	Benign	0.24
Sift	Benign	0.22	T
Sift4G	Benign	0.29	T
Polyphen		0.98	D
Vest4		0.42
MutPred		0.61		Loss of sheet (P = 0.0357)
MVP		0.29
MPC		0.68
ClinPred		0.97	D
GERP RS		-2.3
Varity_R		0.74
gMVP		0.75
Mutation Taster		=89/11	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs372866009; hg19: chr6-107019974;