chr11-63719914-T-C

Position:

• chr11-63719914-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000377819.10(RTN3):​c.1412T>C​(p.Val471Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.795 in 1,613,932 control chromosomes in the GnomAD database, including 516,213 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 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 0.73 (42226 hom., cov: 32)
  • Exomes 𝑓: 0.80 (473987 hom.)
• Consequence: RTN3 ENST00000377819.10 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0730

Genes affected

RTN3 (HGNC:10469): (reticulon 3) This gene belongs to the reticulon family of highly conserved genes that are preferentially expressed in neuroendocrine tissues. This family of proteins interact with, and modulate the activity of beta-amyloid converting enzyme 1 (BACE1), and the production of amyloid-beta. An increase in the expression of any reticulon protein substantially reduces the production of amyloid-beta, suggesting that reticulon proteins are negative modulators of BACE1 in cells. Alternatively spliced transcript variants encoding different isoforms have been found for this gene, and pseudogenes of this gene are located on chromosomes 4 and 12. [provided by RefSeq, May 2012]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=5.7710696E-7).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.963 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RTN3	NM_001265589.2	c.1412T>C	p.Val471Ala	missense_variant	3/9	ENST00000377819.10	NP_001252518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RTN3	ENST00000377819.10	c.1412T>C	p.Val471Ala	missense_variant	3/9	1	NM_001265589.2	ENSP00000367050

Frequencies

GnomAD3 genomes AF: 0.726 AC: 110409 AN: 151978 Hom.: 42216 Cov.: 32

Gnomad AFR AF: 0.468

Gnomad AMI AF: 0.825

Gnomad AMR AF: 0.845

Gnomad ASJ AF: 0.753

Gnomad EAS AF: 0.985

Gnomad SAS AF: 0.721

Gnomad FIN AF: 0.899

Gnomad MID AF: 0.722

Gnomad NFE AF: 0.807

Gnomad OTH AF: 0.753

GnomAD3 exomes AF: 0.806 AC: 202756 AN: 251410 Hom.: 83469 AF XY: 0.804 AC XY: 109184 AN XY: 135884

Gnomad AFR exome AF: 0.457

Gnomad AMR exome AF: 0.901

Gnomad ASJ exome AF: 0.765

Gnomad EAS exome AF: 0.988

Gnomad SAS exome AF: 0.727

Gnomad FIN exome AF: 0.896

Gnomad NFE exome AF: 0.807

Gnomad OTH exome AF: 0.800

GnomAD4 exome AF: 0.802 AC: 1172129 AN: 1461836 Hom.: 473987 Cov.: 66 AF XY: 0.800 AC XY: 581634 AN XY: 727222

Gnomad4 AFR exome AF: 0.449

Gnomad4 AMR exome AF: 0.895

Gnomad4 ASJ exome AF: 0.758

Gnomad4 EAS exome AF: 0.989

Gnomad4 SAS exome AF: 0.727

Gnomad4 FIN exome AF: 0.891

Gnomad4 NFE exome AF: 0.805

Gnomad4 OTH exome AF: 0.792

GnomAD4 genome AF: 0.726 AC: 110454 AN: 152096 Hom.: 42226 Cov.: 32 AF XY: 0.735 AC XY: 54676 AN XY: 74360

Gnomad4 AFR AF: 0.468

Gnomad4 AMR AF: 0.845

Gnomad4 ASJ AF: 0.753

Gnomad4 EAS AF: 0.985

Gnomad4 SAS AF: 0.721

Gnomad4 FIN AF: 0.899

Gnomad4 NFE AF: 0.807

Gnomad4 OTH AF: 0.755

Alfa AF: 0.793 Hom.: 117837

Bravo AF: 0.714

TwinsUK AF: 0.805 AC: 2986

ALSPAC AF: 0.805 AC: 3103

ESP6500AA AF: 0.480 AC: 2112

ESP6500EA AF: 0.802 AC: 6891

ExAC AF: 0.793 AC: 96343

Asia WGS AF: 0.825 AC: 2869 AN: 3478

EpiCase AF: 0.797

EpiControl AF: 0.803

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.73	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	2.9
DANN	Benign	0.53
DEOGEN2	Benign	0.020	T;.;.
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.046	N
LIST_S2	Benign	0.34	T;T;T
MetaRNN	Benign	5.8e-7	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.83	L;.;.
MutationTaster	Benign	1.0	P;P;P;P;P;P;P
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.85	N;N;N
REVEL	Benign	0.031
Sift	Benign	0.56	T;T;T
Sift4G	Benign	0.49	T;T;T
Polyphen		0.0020	B;B;.
Vest4		0.020
MPC		0.069
ClinPred		0.0087	T
GERP RS		-2.9
Varity_R		0.034
gMVP		0.013

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: rs542998; hg19: chr11-63487386;