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
NM_001034850.3 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: -0.593
Publications
3 publications found
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]
Genome browser will be placed here
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 VariationId is 21257.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Variant Effect in Transcripts
ACMG analysis was done for transcript: NM_001034850.3. You can select a different transcript below to see updated ACMG assignments.
RefSeq Transcripts
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| RETREG1 | NM_001034850.3 | MANE Select | c.18_19delTC | p.Pro7GlyfsTer133 | frameshift | Exon 1 of 9 | NP_001030022.1 | ||
| RETREG1-AS1 | NR_109946.1 | n.561+468_561+469delAG | intron | N/A |
Ensembl Transcripts
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| RETREG1 | ENST00000306320.10 | TSL:1 MANE Select | c.18_19delTC | p.Pro7GlyfsTer133 | frameshift | Exon 1 of 9 | ENSP00000304642.9 | ||
| RETREG1 | ENST00000682229.1 | c.18_19delTC | p.Pro7GlyfsTer133 | frameshift | Exon 1 of 10 | ENSP00000507342.1 | |||
| RETREG1 | ENST00000682564.1 | c.18_19delTC | p.Pro7GlyfsTer133 | frameshift | Exon 1 of 9 | ENSP00000508099.1 |
Frequencies
GnomAD3 genomes 0.00000659 AC: 1AN: 151792Hom.: 0 Cov.: 32 show subpopulations
GnomAD3 genomes
AF:
AC:
1
AN:
151792
Hom.:
Cov.:
32
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD4 exome AF: 0.00000697 AC: 9AN: 1292108Hom.: 0 AF XY: 0.0000126 AC XY: 8AN XY: 635298 show subpopulations
GnomAD4 exome
AF:
AC:
9
AN:
1292108
Hom.:
AF XY:
AC XY:
8
AN XY:
635298
show subpopulations
African (AFR)
AF:
AC:
0
AN:
26030
American (AMR)
AF:
AC:
0
AN:
23370
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
22062
East Asian (EAS)
AF:
AC:
0
AN:
27908
South Asian (SAS)
AF:
AC:
0
AN:
68196
European-Finnish (FIN)
AF:
AC:
0
AN:
31954
Middle Eastern (MID)
AF:
AC:
0
AN:
3828
European-Non Finnish (NFE)
AF:
AC:
8
AN:
1035492
Other (OTH)
AF:
AC:
1
AN:
53268
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.458
Heterozygous variant carriers
0
1
2
3
4
5
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Age Distribution
Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
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>80
Age
GnomAD4 genome 0.00000659 AC: 1AN: 151792Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74138 show subpopulations
GnomAD4 genome
AF:
AC:
1
AN:
151792
Hom.:
Cov.:
32
AF XY:
AC XY:
0
AN XY:
74138
show subpopulations
African (AFR)
AF:
AC:
0
AN:
41390
American (AMR)
AF:
AC:
0
AN:
15234
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
3472
East Asian (EAS)
AF:
AC:
0
AN:
5166
South Asian (SAS)
AF:
AC:
0
AN:
4836
European-Finnish (FIN)
AF:
AC:
0
AN:
10456
Middle Eastern (MID)
AF:
AC:
0
AN:
314
European-Non Finnish (NFE)
AF:
AC:
1
AN:
67922
Other (OTH)
AF:
AC:
0
AN:
2090
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.425
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Alfa
AF:
Hom.:
Bravo
AF:
ClinVar
ClinVar submissions as Germline
Significance:Pathogenic
Revision:criteria provided, multiple submitters, no conflicts
Pathogenic
VUS
Benign
Condition
2
-
-
not provided (2)
-
1
-
Charcot-Marie-Tooth disease (1)
-
1
-
Hereditary sensory and autonomic neuropathy type 2 (1)
1
-
-
Inborn genetic diseases (1)
1
-
-
Neuropathy, hereditary sensory and autonomic, type 2B (1)
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
PhyloP100
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
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