chr14-59727615-T-C

Position:

• chr14-59727615-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_021136.3(RTN1):​c.1069A>G​(p.Ile357Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00286 in 1,612,624 control chromosomes in the GnomAD database, including 126 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.015 (61 hom., cov: 32)
  • Exomes 𝑓: 0.0016 (65 hom.)
• Consequence: RTN1 NM_021136.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.14

Genes affected

RTN1 (HGNC:10467): (reticulon 1) 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. This gene is considered to be a specific marker for neurological diseases and cancer, and is a potential molecular target for therapy. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2011]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0021155477).
• BP6: Variant 14-59727615-T-C is Benign according to our data. Variant chr14-59727615-T-C is described in ClinVar as [Benign]. Clinvar id is 781130.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0508 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RTN1	NM_021136.3	c.1069A>G	p.Ile357Val	missense_variant	3/9	ENST00000267484.10	NP_066959.1
RTN1	XM_011537063.4	c.1069A>G	p.Ile357Val	missense_variant	3/4		XP_011535365.1
RTN1	XM_047431674.1	c.1069A>G	p.Ile357Val	missense_variant	3/4		XP_047287630.1
RTN1	XR_007064042.1	n.1215A>G		non_coding_transcript_exon_variant	3/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RTN1	ENST00000267484.10	c.1069A>G	p.Ile357Val	missense_variant	3/9	1	NM_021136.3	ENSP00000267484
RTN1	ENST00000432103.6	n.99A>G		non_coding_transcript_exon_variant	1/7	1

Frequencies

GnomAD3 genomes AF: 0.0151 AC: 2294 AN: 152126 Hom.: 61 Cov.: 32

Gnomad AFR AF: 0.0525

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00484

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.0120

GnomAD3 exomes AF: 0.00397 AC: 984 AN: 247898 Hom.: 28 AF XY: 0.00310 AC XY: 418 AN XY: 134666

Gnomad AFR exome AF: 0.0541

Gnomad AMR exome AF: 0.00204

Gnomad ASJ exome AF: 0.00222

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000329

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000241

Gnomad OTH exome AF: 0.00182

GnomAD4 exome AF: 0.00158 AC: 2307 AN: 1460380 Hom.: 65 Cov.: 31 AF XY: 0.00136 AC XY: 988 AN XY: 726486

Gnomad4 AFR exome AF: 0.0553

Gnomad4 AMR exome AF: 0.00236

Gnomad4 ASJ exome AF: 0.00180

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000963

Gnomad4 OTH exome AF: 0.00308

GnomAD4 genome AF: 0.0152 AC: 2309 AN: 152244 Hom.: 61 Cov.: 32 AF XY: 0.0148 AC XY: 1099 AN XY: 74424

Gnomad4 AFR AF: 0.0527

Gnomad4 AMR AF: 0.00484

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000235

Gnomad4 OTH AF: 0.0118

Alfa AF: 0.00276 Hom.: 18

Bravo AF: 0.0174

ESP6500AA AF: 0.0525 AC: 231

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00485 AC: 589

Asia WGS AF: 0.00318 AC: 12 AN: 3478

EpiCase AF: 0.000327

EpiControl AF: 0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 26, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	15
DANN	Uncertain	0.99
DEOGEN2	Benign	0.013	T;T
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.11
FATHMM_MKL	Benign	0.72	D
LIST_S2	Benign	0.75	T;T
MetaRNN	Benign	0.0021	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.0	M;.
MutationTaster	Benign	0.95	D
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-0.28	N;.
REVEL	Benign	0.060
Sift	Benign	0.14	T;.
Sift4G	Benign	0.46	T;T
Polyphen		0.067	B;.
Vest4		0.24
MVP		0.068
MPC		0.086
ClinPred		0.0060	T
GERP RS		3.2
Varity_R		0.048
gMVP		0.18

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs35707243; hg19: chr14-60194333;