chr2-55027029-T-A

Variant names:

• chr2-55027029-T-A
• rs11677099
• NM_020532.5:c.1070A>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_020532.5(RTN4):​c.1070A>T​(p.Asp357Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0236 in 1,613,542 control chromosomes in the GnomAD database, including 551 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.019 (53 hom., cov: 32)
  • Exomes 𝑓: 0.024 (498 hom.)
• Consequence: RTN4 NM_020532.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.43
• Publications: 19 publications found

Genes affected

RTN4 (HGNC:14085): (reticulon 4) This gene belongs to the family of reticulon encoding genes. Reticulons are associated with the endoplasmic reticulum, and are involved in neuroendocrine secretion or in membrane trafficking in neuroendocrine cells. The product of this gene is a potent neurite outgrowth inhibitor which may also help block the regeneration of the central nervous system in higher vertebrates. Alternatively spliced transcript variants derived both from differential splicing and differential promoter usage and encoding different isoforms have been identified. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0020200014).
• BA1: GnomAdExome4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0547 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020532.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RTN4	NM_020532.5	MANE Select	c.1070A>T	p.Asp357Val	missense	Exon 3 of 9	NP_065393.1
	RTN4	NM_001321859.2		c.452A>T	p.Asp151Val	missense	Exon 3 of 9	NP_001308788.1
	RTN4	NM_001321860.1		c.452A>T	p.Asp151Val	missense	Exon 3 of 9	NP_001308789.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RTN4	ENST00000337526.11	TSL:1 MANE Select	c.1070A>T	p.Asp357Val	missense	Exon 3 of 9	ENSP00000337838.6
	RTN4	ENST00000357376.7	TSL:1	c.452A>T	p.Asp151Val	missense	Exon 3 of 9	ENSP00000349944.3
	RTN4	ENST00000394611.6	TSL:1	c.452A>T	p.Asp151Val	missense	Exon 3 of 9	ENSP00000378109.2

Frequencies

GnomAD3 genomes AF: 0.0195 AC: 2969 AN: 152186 Hom.: 53 Cov.: 32

Gnomad AFR AF: 0.00466

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.0168

Gnomad ASJ AF: 0.0199

Gnomad EAS AF: 0.0510

Gnomad SAS AF: 0.0196

Gnomad FIN AF: 0.0329

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0248

Gnomad OTH AF: 0.0206

GnomAD2 exomes AF: 0.0224 AC: 5622 AN: 250684 AF XY: 0.0228

Gnomad AFR exome AF: 0.00419

Gnomad AMR exome AF: 0.00992

Gnomad ASJ exome AF: 0.0187

Gnomad EAS exome AF: 0.0541

Gnomad FIN exome AF: 0.0303

Gnomad NFE exome AF: 0.0242

Gnomad OTH exome AF: 0.0201

GnomAD4 exome AF: 0.0241 AC: 35189 AN: 1461238 Hom.: 498 Cov.: 34 AF XY: 0.0241 AC XY: 17545 AN XY: 726950

African (AFR) AF: 0.00365 AC: 122 AN: 33460

American (AMR) AF: 0.0107 AC: 479 AN: 44666

Ashkenazi Jewish (ASJ) AF: 0.0207 AC: 541 AN: 26122

East Asian (EAS) AF: 0.0567 AC: 2248 AN: 39680

South Asian (SAS) AF: 0.0174 AC: 1498 AN: 86248

European-Finnish (FIN) AF: 0.0296 AC: 1573 AN: 53116

Middle Eastern (MID) AF: 0.0127 AC: 73 AN: 5766

European-Non Finnish (NFE) AF: 0.0244 AC: 27146 AN: 1111804

Other (OTH) AF: 0.0250 AC: 1509 AN: 60376

GnomAD4 genome AF: 0.0195 AC: 2968 AN: 152304 Hom.: 53 Cov.: 32 AF XY: 0.0197 AC XY: 1467 AN XY: 74480

African (AFR) AF: 0.00464 AC: 193 AN: 41576

American (AMR) AF: 0.0168 AC: 256 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.0199 AC: 69 AN: 3466

East Asian (EAS) AF: 0.0511 AC: 265 AN: 5182

South Asian (SAS) AF: 0.0197 AC: 95 AN: 4832

European-Finnish (FIN) AF: 0.0329 AC: 349 AN: 10618

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.0248 AC: 1688 AN: 68030

Other (OTH) AF: 0.0204 AC: 43 AN: 2112

Alfa AF: 0.0221 Hom.: 35

Bravo AF: 0.0169

TwinsUK AF: 0.0245 AC: 91

ALSPAC AF: 0.0234 AC: 90

ESP6500AA AF: 0.00454 AC: 20

ESP6500EA AF: 0.0247 AC: 212

ExAC AF: 0.0224 AC: 2715

Asia WGS AF: 0.0370 AC: 127 AN: 3478

EpiCase AF: 0.0238

EpiControl AF: 0.0232

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	18
DANN	Uncertain	0.98
DEOGEN2	Benign	0.24	T
Eigen	Benign	-0.11
Eigen_PC	Benign	-0.25
FATHMM_MKL	Benign	0.55	D
LIST_S2	Benign	0.47	T
MetaRNN	Benign	0.0020	T
MetaSVM	Benign	-1.2	T
MutationAssessor	Benign	2.0	M
PhyloP100		1.4
PrimateAI	Benign	0.28	T
PROVEAN	Uncertain	-2.6	D
REVEL	Benign	0.15
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0040	D
Polyphen		0.99	D
Vest4		0.14
MPC		0.12
ClinPred		0.036	T
GERP RS		3.9
Varity_R		0.24
gMVP		0.087
Mutation Taster		=97/3	polymorphism (auto)

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: rs11677099; hg19: chr2-55254165; COSMIC: COSV58265867; COSMIC: COSV58265867;