Variant rs137852736 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong

The NM_001034850.3(RETREG1):c.18_19delTC(p.Pro7fs) 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 (★★).

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

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:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 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. Fraction of 0.988 CDS is truncated, and there are 3 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. Variant chr5-16616952-GGA-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RETREG1	NM_001034850.3 linkuse as main transcript	c.18_19delTC	p.Pro7fs	frameshift_variant	1/9	ENST00000306320.10	NP_001030022.1	Q9H6L5-1
RETREG1	XM_011514053.4 linkuse as main transcript	c.18_19delTC	p.Pro7fs	frameshift_variant	1/10		XP_011512355.1
RETREG1-AS1	NR_109946.1 linkuse as main transcript	n.561+468_561+469delAG		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RETREG1	ENST00000306320.10 linkuse as main transcript	c.18_19delTC	p.Pro7fs	frameshift_variant	1/9	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

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000773

Gnomad4 OTH exome

AF:

0.0000188

GnomAD4 genome

AF:

0.00000659

AC:

AN:

151792

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74138

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

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

Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Apr 22, 2022	PM2, PM3_supporting, PVS1 -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 12, 2022	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 21257). This premature translational stop signal has been observed in individual(s) with hereditary sensory and autonomic neuropathy (PMID: 19838196). This variant is not present in population databases (gnomAD no frequency). 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). -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 24, 2020

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

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 01, 2009

- -

Charcot-Marie-Tooth disease

Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

Inherited Neuropathy Consortium

- -

Hereditary sensory and autonomic neuropathy type 2

Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

Inherited Neuropathy Consortium Ii, University Of Miami

Feb 17, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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