5-16572044-G-A

Position:

chr5-16572044-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001034850.3(RETREG1):c.379C>T(p.Arg127Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00723 in 1,613,468 control chromosomes in the GnomAD database, including 56 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R127H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0057 ( 4 hom., cov: 32)

Exomes 𝑓: 0.0074 ( 52 hom. )

Consequence

RETREG1
NM_001034850.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 1.73

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009130418).

BP6

Variant 5-16572044-G-A is Benign according to our data. Variant chr5-16572044-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 377837.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-16572044-G-A is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00572 (870/152102) while in subpopulation NFE AF= 0.00799 (543/67998). AF 95% confidence interval is 0.00743. There are 4 homozygotes in gnomad4. There are 452 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RETREG1	NM_001034850.3 linkuse as main transcript	c.379C>T	p.Arg127Cys	missense_variant	2/9	ENST00000306320.10
RETREG1	XM_011514053.4 linkuse as main transcript	c.379C>T	p.Arg127Cys	missense_variant	2/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RETREG1	ENST00000306320.10 linkuse as main transcript	c.379C>T	p.Arg127Cys	missense_variant	2/9	1	NM_001034850.3		Q9H6L5-1

Frequencies

GnomAD3 genomes

AF:

0.00572

AC:

870

AN:

151984

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00147

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00393

Gnomad ASJ

AF:

0.00260

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0180

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00798

Gnomad OTH

AF:

0.00335

GnomAD3 exomes

AF:

0.00642

AC:

1602

AN:

249488

Hom.:

AF XY:

0.00624

AC XY:

845

AN XY:

135352

show subpopulations

Gnomad AFR exome

AF:

0.00103

Gnomad AMR exome

AF:

0.00281

Gnomad ASJ exome

AF:

0.00169

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000229

Gnomad FIN exome

AF:

0.0155

Gnomad NFE exome

AF:

0.00956

Gnomad OTH exome

AF:

0.00793

GnomAD4 exome

AF:

0.00739

AC:

10799

AN:

1461366

Hom.:

Cov.:

AF XY:

0.00709

AC XY:

5156

AN XY:

727034

show subpopulations

Gnomad4 AFR exome

AF:

0.000986

Gnomad4 AMR exome

AF:

0.00266

Gnomad4 ASJ exome

AF:

0.00134

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000185

Gnomad4 FIN exome

AF:

0.0157

Gnomad4 NFE exome

AF:

0.00842

Gnomad4 OTH exome

AF:

0.00654

GnomAD4 genome

AF:

0.00572

AC:

870

AN:

152102

Hom.:

Cov.:

AF XY:

0.00608

AC XY:

452

AN XY:

74378

show subpopulations

Gnomad4 AFR

AF:

0.00147

Gnomad4 AMR

AF:

0.00392

Gnomad4 ASJ

AF:

0.00260

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0180

Gnomad4 NFE

AF:

0.00799

Gnomad4 OTH

AF:

0.00331

Alfa

AF:

0.00673

Hom.:

Bravo

AF:

0.00437

TwinsUK

AF:

0.00593

AC:

ALSPAC

AF:

0.00856

AC:

ESP6500AA

AF:

0.000806

AC:

ESP6500EA

AF:

0.00792

AC:

ExAC

AF:

0.00700

AC:

846

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00687

EpiControl

AF:

0.00557

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Neuropathy, hereditary sensory and autonomic, type 2B

Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	RETREG1: BS2 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

RETREG1-related disorder

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 22, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Oct 19, 2016

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 22, 2020

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.45

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0051

Eigen

Benign

-0.36

Eigen_PC

Benign

-0.18

FATHMM_MKL

Benign

0.29

LIST_S2

Benign

0.77

MetaRNN

Benign

0.0091

MetaSVM

Benign

-1.1

MutationTaster

Benign

0.98

PrimateAI

Uncertain

0.59

PROVEAN

Benign

0.23

REVEL

Benign

0.079

Sift

Benign

0.16

Sift4G

Benign

0.21

Polyphen

0.027

Vest4

0.43

MVP

0.47

MPC

0.45

ClinPred

0.016

GERP RS

4.0

Varity_R

0.058

gMVP

0.47

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over