Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The ENST00000306320.10(RETREG1):c.19C>T(p.Pro7Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000278 in 1,438,628 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P7A) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000026 ( 0 hom. )

Consequence

RETREG1
ENST00000306320.10 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: -0.783

Publications

1 publications found

Variant links:

Genes affected

RETREG1 (HGNC:25964): (reticulophagy regulator 1) The protein encoded by this gene is a cis-Golgi transmembrane protein that may be necessary for the long-term survival of nociceptive and autonomic ganglion neurons. Mutations in this gene are a cause of hereditary sensory and autonomic neuropathy type IIB (HSAN IIB), and this gene may also play a role in susceptibility to vascular dementia. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Nov 2011]

RETREG1 links:

RETREG1-AS1 (HGNC:55551): (RETREG1 antisense RNA 1)

RETREG1-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.031914085).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000306320.10. 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
	RETREG1	NM_001034850.3	MANE Select	c.19C>T	p.Pro7Ser	missense	Exon 1 of 9	NP_001030022.1
	RETREG1-AS1	NR_109946.1		n.561+467G>A		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
RETREG1	ENST00000306320.10	TSL:1 MANE Select	c.19C>T	p.Pro7Ser	missense	Exon 1 of 9	ENSP00000304642.9
RETREG1	ENST00000682229.1		c.19C>T	p.Pro7Ser	missense	Exon 1 of 10	ENSP00000507342.1
RETREG1	ENST00000682564.1		c.19C>T	p.Pro7Ser	missense	Exon 1 of 9	ENSP00000508099.1

Frequencies

GnomAD3 genomes

AF:

0.0000461

AC:

AN:

151770

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000725

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000194

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000150

AC:

AN:

66724

AF XY:

0.0000257

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000381

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000256

AC:

AN:

1286858

Hom.:

Cov.:

AF XY:

0.0000253

AC XY:

AN XY:

632834

show subpopulations

African (AFR)

AF:

0.0000386

AC:

AN:

25924

American (AMR)

AF:

0.00

AC:

AN:

23356

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22030

East Asian (EAS)

AF:

0.00

AC:

AN:

27862

South Asian (SAS)

AF:

0.000117

AC:

AN:

68120

European-Finnish (FIN)

AF:

0.00

AC:

AN:

31962

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3816

European-Non Finnish (NFE)

AF:

0.0000233

AC:

AN:

1030734

Other (OTH)

AF:

0.00

AC:

AN:

53054

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.510

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000461

AC:

AN:

151770

Hom.:

Cov.:

AF XY:

0.0000810

AC XY:

AN XY:

74108

show subpopulations

African (AFR)

AF:

0.0000725

AC:

AN:

41386

American (AMR)

AF:

0.000131

AC:

AN:

15228

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000194

AC:

AN:

5160

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10454

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

67924

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000869

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Inborn genetic diseases (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.088

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.71

CADD

Benign

1.8

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.0042

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.024

LIST_S2

Benign

0.28

M_CAP

Benign

0.040

MetaRNN

Benign

0.032

MetaSVM

Benign

-1.0

PhyloP100

-0.78

PrimateAI

Uncertain

0.72

PROVEAN

Benign

0.15

REVEL

Benign

0.017

Sift

Benign

0.074

Sift4G

Benign

0.33

Polyphen

0.0

Vest4

0.10

MutPred

0.19

Gain of phosphorylation at P7 (P = 0.0055)

MVP

0.13

MPC

0.33

ClinPred

0.040

GERP RS

-0.63

PromoterAI

-0.018

Neutral

(source)

Varity_R

0.021

gMVP

0.22

Mutation Taster

=95/5

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

rs532140281

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over