GeneBe

rs886037748

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1PM2

The NM_001034850.3(RETREG1):​c.826delA​(p.Ser276ValfsTer8) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,458,754 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

RETREG1
NM_001034850.3 frameshift

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity no assertion criteria provided P:1U:2

Conservation

PhyloP100: 2.02
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]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
RETREG1NM_001034850.3 linkc.826delA p.Ser276ValfsTer8 frameshift_variant Exon 7 of 9 ENST00000306320.10 NP_001030022.1 Q9H6L5-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
RETREG1ENST00000306320.10 linkc.826delA p.Ser276ValfsTer8 frameshift_variant Exon 7 of 9 1 NM_001034850.3 ENSP00000304642.9 Q9H6L5-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
6.86e-7
AC:
1
AN:
1458754
Hom.:
0
Cov.:
31
AF XY:
0.00000138
AC XY:
1
AN XY:
725668
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:
9.01e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:2
Revision: no assertion criteria provided
LINK: link

Submissions by phenotype

Neuropathy, hereditary sensory and autonomic, type 2B Pathogenic:1
May 01, 2014
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
Dec 08, 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

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.17
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.

Other links and lift over

dbSNP: rs886037748; hg19: chr5-16478189; API