rs894277583

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_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. 13/21 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. P6T) has been classified 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

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 -5 ACMG points.

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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RETREG1	NM_001034850.3 link	c.17C>T	p.Pro6Leu	missense_variant	Exon 1 of 9	ENST00000306320.10	NP_001030022.1	Q9H6L5-1
RETREG1	XM_011514053.4 link	c.17C>T	p.Pro6Leu	missense_variant	Exon 1 of 10		XP_011512355.1
RETREG1-AS1	NR_109946.1 link	n.561+469G>A		intron_variant	Intron 1 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RETREG1	ENST00000306320.10 link	c.17C>T	p.Pro6Leu	missense_variant	Exon 1 of 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

GnomAD2 exomes

AF:

0.000395

AC:

AN:

65808

AF XY:

0.000313

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 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

African (AFR)

AF:

0.00

AC:

AN:

25872

American (AMR)

AF:

0.00194

AC:

AN:

23144

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

21962

East Asian (EAS)

AF:

0.0000359

AC:

AN:

27820

South Asian (SAS)

AF:

0.0000147

AC:

AN:

67842

European-Finnish (FIN)

AF:

0.00

AC:

AN:

31900

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3810

European-Non Finnish (NFE)

AF:

0.0000485

AC:

AN:

1029942

Other (OTH)

AF:

0.000208

AC:

AN:

52974

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

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:

0.000244

AC:

AN:

151894

Hom.:

Cov.:

AF XY:

0.000242

AC XY:

AN XY:

74242

show subpopulations

African (AFR)

AF:

0.0000723

AC:

AN:

41520

American (AMR)

AF:

0.00157

AC:

AN:

15254

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000194

AC:

AN:

5152

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10448

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0000736

AC:

AN:

67900

Other (OTH)

AF:

0.00189

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.511

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:

0.0000712

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

Jan 01, 2020

CeGaT Center for Human Genetics Tuebingen

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 03, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

May 03, 2021

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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) -

Inborn genetic diseases

Uncertain:1

Jul 09, 2021

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Apr 28, 2017

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

(source)

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

PhyloP100

0.35

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

PromoterAI

0.46

Neutral

(source)

Varity_R

0.13

gMVP

0.27

Mutation Taster

=94/6

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over