11-63719914-T-C

Variant names:

• chr11-63719914-T-C
• rs542998
• NM_001265589.2:c.1412T>C

Variant summary

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

The NM_001265589.2(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. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V471G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.73 (42226 hom., cov: 32)
  • Exomes 𝑓: 0.80 (473987 hom.)
• Consequence: RTN3 NM_001265589.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0730
• Publications: 47 publications found

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

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001265589.2. 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
	RTN3	NM_001265589.2	MANE Select	c.1412T>C	p.Val471Ala	missense	Exon 3 of 9	NP_001252518.1	O95197-1
	RTN3	NM_201428.3		c.1355T>C	p.Val452Ala	missense	Exon 2 of 8	NP_958831.1	O95197-2
	RTN3	NM_001265590.2		c.1076T>C	p.Val359Ala	missense	Exon 2 of 8	NP_001252519.1	O95197-7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RTN3	ENST00000377819.10	TSL:1 MANE Select	c.1412T>C	p.Val471Ala	missense	Exon 3 of 9	ENSP00000367050.5	O95197-1
	RTN3	ENST00000339997.8	TSL:1	c.1355T>C	p.Val452Ala	missense	Exon 2 of 8	ENSP00000344106.4	O95197-2
	RTN3	ENST00000540798.5	TSL:1	c.1076T>C	p.Val359Ala	missense	Exon 2 of 8	ENSP00000442733.1	O95197-7

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

GnomAD2 exomes AF: 0.806 AC: 202756 AN: 251410 AF XY: 0.804

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 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

African (AFR) AF: 0.449 AC: 15044 AN: 33478

American (AMR) AF: 0.895 AC: 40044 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.758 AC: 19817 AN: 26134

East Asian (EAS) AF: 0.989 AC: 39265 AN: 39698

South Asian (SAS) AF: 0.727 AC: 62696 AN: 86252

European-Finnish (FIN) AF: 0.891 AC: 47619 AN: 53418

Middle Eastern (MID) AF: 0.744 AC: 4290 AN: 5766

European-Non Finnish (NFE) AF: 0.805 AC: 895540 AN: 1111972

Other (OTH) AF: 0.792 AC: 47814 AN: 60394

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

African (AFR) AF: 0.468 AC: 19366 AN: 41408

American (AMR) AF: 0.845 AC: 12927 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.753 AC: 2613 AN: 3470

East Asian (EAS) AF: 0.985 AC: 5106 AN: 5182

South Asian (SAS) AF: 0.721 AC: 3476 AN: 4824

European-Finnish (FIN) AF: 0.899 AC: 9534 AN: 10602

Middle Eastern (MID) AF: 0.724 AC: 213 AN: 294

European-Non Finnish (NFE) AF: 0.807 AC: 54874 AN: 68004

Other (OTH) AF: 0.755 AC: 1593 AN: 2110

Alfa AF: 0.777 Hom.: 163974

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 v4.9

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
MetaRNN	Benign	5.8e-7	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.83	L
PhyloP100		-0.073
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.85	N
REVEL	Benign	0.031
Sift	Benign	0.56	T
Sift4G	Benign	0.49	T
Polyphen		0.0020	B
Vest4		0.020
MPC		0.069
ClinPred		0.0087	T
GERP RS		-2.9
Varity_R		0.034
gMVP		0.013
Mutation Taster		=100/0	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: rs542998; hg19: chr11-63487386; COSMIC: COSV107408139; COSMIC: COSV107408139;