rs894277583

Positions:

chr5-16616955-G-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBS1_Supporting

The NM_001034850.3(RETREG1):c.17C>T(p.Pro6Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000101 in 1,437,160 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00024 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000084 ( 0 hom. )

Consequence

RETREG1
NM_001034850.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:5

Conservation

PhyloP100: 0.354

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 (HGNC:):

RETREG1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.018291533).

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000244 (37/151894) while in subpopulation AMR AF= 0.00157 (24/15254). AF 95% confidence interval is 0.00108. There are 0 homozygotes in gnomad4. There are 18 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RETREG1	NM_001034850.3 linkuse as main transcript	c.17C>T	p.Pro6Leu	missense_variant	1/9	ENST00000306320.10	NP_001030022.1	Q9H6L5-1
RETREG1	XM_011514053.4 linkuse as main transcript	c.17C>T	p.Pro6Leu	missense_variant	1/10		XP_011512355.1
RETREG1-AS1	NR_109946.1 linkuse as main transcript	n.561+469G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RETREG1	ENST00000306320.10 linkuse as main transcript	c.17C>T	p.Pro6Leu	missense_variant	1/9	1	NM_001034850.3	ENSP00000304642.9		Q9H6L5-1

Frequencies

GnomAD3 genomes

AF:

0.000244

AC:

AN:

151786

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000725

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00158

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000736

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.000395

AC:

AN:

65808

Hom.:

AF XY:

0.000313

AC XY:

AN XY:

38350

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00208

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000526

GnomAD4 exome

AF:

0.0000840

AC:

108

AN:

1285266

Hom.:

Cov.:

AF XY:

0.0000807

AC XY:

AN XY:

631970

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00194

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000359

Gnomad4 SAS exome

AF:

0.0000147

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000485

Gnomad4 OTH exome

AF:

0.000208

GnomAD4 genome

AF:

0.000244

AC:

AN:

151894

Hom.:

Cov.:

AF XY:

0.000242

AC XY:

AN XY:

74242

show subpopulations

Gnomad4 AFR

AF:

0.0000723

Gnomad4 AMR

AF:

0.00157

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000194

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000736

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.000465

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	May 03, 2021	In silico analysis supports that this missense variant does not alter protein structure/function; Reported previously as a homozygous variant in an individual with paclitaxel-induced peripheral neuropathy; however, additional information was not provided (Apellaniz-Ruiz et al., 2016); This variant is associated with the following publications: (PMID: 27582484) -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 03, 2022	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 6 of the RETREG1 protein (p.Pro6Leu). This variant is present in population databases (no rsID available, gnomAD 0.2%). This variant has not been reported in the literature in individuals affected with RETREG1-related conditions. ClinVar contains an entry for this variant (Variation ID: 538125). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 09, 2021

The c.17C>T (p.P6L) alteration is located in exon 1 (coding exon 1) of the FAM134B gene. This alteration results from a C to T substitution at nucleotide position 17, causing the proline (P) at amino acid position 6 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Neuropathy, hereditary sensory and autonomic, type 2B

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 28, 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 did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.52

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.012

Eigen

Benign

-0.56

Eigen_PC

Benign

-0.51

FATHMM_MKL

Benign

0.16

LIST_S2

Benign

0.61

M_CAP

Benign

0.078

MetaRNN

Benign

0.018

MetaSVM

Benign

-1.0

PrimateAI

Pathogenic

0.81

PROVEAN

Benign

-0.83

REVEL

Benign

0.054

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

0.0080

Vest4

0.21

MutPred

0.15

Loss of glycosylation at P6 (P = 0.0235);

MVP

0.50

MPC

0.34

ClinPred

0.28

GERP RS

3.0

Varity_R

0.13

gMVP

0.27

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