rs137852736

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_001034850.3(RETREG1):c.18_19delTC(p.Pro7GlyfsTer133) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000693 in 1,443,900 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. P6P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000070 ( 0 hom. )

Consequence

RETREG1
NM_001034850.3 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:4U:2

Conservation

PhyloP100: -0.593

Publications

3 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:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 18 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 21 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 5-16616952-GGA-G is Pathogenic according to our data. Variant chr5-16616952-GGA-G is described in ClinVar as [Pathogenic]. Clinvar id is 21257.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RETREG1	NM_001034850.3 link	c.18_19delTC	p.Pro7GlyfsTer133	frameshift_variant	Exon 1 of 9	ENST00000306320.10	NP_001030022.1	Q9H6L5-1
RETREG1	XM_011514053.4 link	c.18_19delTC	p.Pro7GlyfsTer133	frameshift_variant	Exon 1 of 10		XP_011512355.1
RETREG1-AS1	NR_109946.1 link	n.561+468_561+469delAG		intron_variant	Intron 1 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RETREG1	ENST00000306320.10 link	c.18_19delTC	p.Pro7GlyfsTer133	frameshift_variant	Exon 1 of 9	1	NM_001034850.3	ENSP00000304642.9		Q9H6L5-1

Frequencies

GnomAD3 genomes

AF:

0.00000659

AC:

AN:

151792

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

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

GnomAD4 exome

AF:

0.00000697

AC:

AN:

1292108

Hom.:

AF XY:

0.0000126

AC XY:

AN XY:

635298

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26030

American (AMR)

AF:

0.00

AC:

AN:

23370

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22062

East Asian (EAS)

AF:

0.00

AC:

AN:

27908

South Asian (SAS)

AF:

0.00

AC:

AN:

68196

European-Finnish (FIN)

AF:

0.00

AC:

AN:

31954

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3828

European-Non Finnish (NFE)

AF:

0.00000773

AC:

AN:

1035492

Other (OTH)

AF:

0.0000188

AC:

AN:

53268

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00000659

AC:

AN:

151792

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74138

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41390

American (AMR)

AF:

0.00

AC:

AN:

15234

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5166

South Asian (SAS)

AF:

0.00

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10456

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

67922

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Apr 22, 2022

Mayo Clinic Laboratories, Mayo Clinic

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PM2, PM3_supporting, PVS1 -

Nov 12, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ClinVar contains an entry for this variant (Variation ID: 21257). For these reasons, this variant has been classified as Pathogenic. This premature translational stop signal has been observed in individual(s) with hereditary sensory and autonomic neuropathy (PMID: 19838196). This sequence change creates a premature translational stop signal (p.Pro7Glyfs*133) in the RETREG1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in RETREG1 are known to be pathogenic (PMID: 19838196). This variant is not present in population databases (gnomAD no frequency). -

Inborn genetic diseases

Pathogenic:1

Nov 24, 2020

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.18_19delTC pathogenic mutation, located in coding exon 1 of the FAM134B gene, results from a deletion of two nucleotides at nucleotide positions 18 to 19, causing a translational frameshift with a predicted alternate stop codon (p.P7Gfs*133). This variant has been described in the homozygous state in an individual with hereditary sensory and autonomic neuropathy type IIB (HSAN2B) (Kurth I et al. Nat Genet, 2009 Nov;41:1179-81). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

Neuropathy, hereditary sensory and autonomic, type 2B

Pathogenic:1

Nov 01, 2009

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Charcot-Marie-Tooth disease

Uncertain:1

Inherited Neuropathy Consortium

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Hereditary sensory and autonomic neuropathy type 2

Uncertain:1

Feb 17, 2019

Inherited Neuropathy Consortium Ii, University Of Miami

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.59

Mutation Taster

=18/182

disease causing (ClinVar)

(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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rs137852736

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over