rs34432513

Positions:

chr5-16475100-G-C

Variant summary

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

The NM_001034850.3(RETREG1):c.1135C>G(p.Gln379Glu) variant causes a missense change. The variant allele was found at a frequency of 0.00205 in 1,613,924 control chromosomes in the GnomAD database, including 55 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.011 ( 24 hom., cov: 31)

Exomes 𝑓: 0.0012 ( 31 hom. )

Consequence

RETREG1
NM_001034850.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 4.12

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=0.002496004).

BP6

Variant 5-16475100-G-C is Benign according to our data. Variant chr5-16475100-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 21255.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-16475100-G-C is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0106 (1607/152232) while in subpopulation AFR AF= 0.0358 (1486/41538). AF 95% confidence interval is 0.0343. There are 24 homozygotes in gnomad4. There are 784 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 24 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RETREG1	NM_001034850.3 link	c.1135C>G	p.Gln379Glu	missense_variant	9/9	ENST00000306320.10	NP_001030022.1	Q9H6L5-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RETREG1	ENST00000306320.10 link	c.1135C>G	p.Gln379Glu	missense_variant	9/9	1	NM_001034850.3	ENSP00000304642.9		Q9H6L5-1

Frequencies

GnomAD3 genomes

AF:

0.0105

AC:

1601

AN:

152114

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0357

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00550

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.000191

Gnomad OTH

AF:

0.00909

GnomAD3 exomes

AF:

0.00266

AC:

663

AN:

248972

Hom.:

AF XY:

0.00218

AC XY:

294

AN XY:

135080

show subpopulations

Gnomad AFR exome

AF:

0.0367

Gnomad AMR exome

AF:

0.00189

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000654

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000151

Gnomad OTH exome

AF:

0.00182

GnomAD4 exome

AF:

0.00116

AC:

1694

AN:

1461692

Hom.:

Cov.:

AF XY:

0.00103

AC XY:

750

AN XY:

727154

show subpopulations

Gnomad4 AFR exome

AF:

0.0391

Gnomad4 AMR exome

AF:

0.00184

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000151

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000935

Gnomad4 OTH exome

AF:

0.00258

GnomAD4 genome

AF:

0.0106

AC:

1607

AN:

152232

Hom.:

Cov.:

AF XY:

0.0105

AC XY:

784

AN XY:

74444

show subpopulations

Gnomad4 AFR

AF:

0.0358

Gnomad4 AMR

AF:

0.00549

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000191

Gnomad4 OTH

AF:

0.00900

Alfa

AF:

0.00155

Hom.:

Bravo

AF:

0.0121

ESP6500AA

AF:

0.0347

AC:

137

ESP6500EA

AF:

0.000240

AC:

ExAC

AF:

0.00329

AC:

398

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.000218

EpiControl

AF:

0.000296

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

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	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Feb 25, 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. -

Neuropathy, hereditary sensory and autonomic, type 2B;C2752089:Neuropathy, hereditary sensory and autonomic, type 2A

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Nov 01, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.074

BayesDel_addAF

Benign

-0.62

BayesDel_noAF

Benign

-0.64

CADD

Benign

DANN

Benign

0.14

DEOGEN2

Benign

0.014

.;T

Eigen

Benign

-0.69

Eigen_PC

Benign

-0.59

FATHMM_MKL

Uncertain

0.76

LIST_S2

Benign

0.81

T;T

MetaRNN

Benign

0.0025

T;T

MetaSVM

Benign

-1.1

PrimateAI

Benign

0.22

PROVEAN

Benign

-0.51

N;N

REVEL

Benign

0.11

Sift

Benign

1.0

T;T

Sift4G

Benign

1.0

T;T

Polyphen

0.034

B;B

Vest4

0.20

MVP

0.38

MPC

0.39

ClinPred

0.0066

GERP RS

3.9

Varity_R

0.045

gMVP

0.11

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

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