rs137852736
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong
The NM_001034850.3(RETREG1):βc.18_19delβ(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 (β β ). Synonymous variant affecting the same amino acid position (i.e. P6P) has been classified as Likely benign.
Frequency
Consequence
NM_001034850.3 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RETREG1 | NM_001034850.3 | c.18_19del | p.Pro7GlyfsTer133 | frameshift_variant | 1/9 | ENST00000306320.10 | |
RETREG1-AS1 | NR_109946.1 | n.561+468_561+469del | intron_variant, non_coding_transcript_variant | ||||
RETREG1 | XM_011514053.4 | c.18_19del | p.Pro7GlyfsTer133 | frameshift_variant | 1/10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RETREG1 | ENST00000306320.10 | c.18_19del | p.Pro7GlyfsTer133 | frameshift_variant | 1/9 | 1 | NM_001034850.3 | ||
RETREG1-AS1 | ENST00000653650.1 | n.329+468_329+469del | intron_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes AF: 0.00000659 AC: 1AN: 151792Hom.: 0 Cov.: 32
GnomAD4 exome AF: 0.00000697 AC: 9AN: 1292108Hom.: 0 AF XY: 0.0000126 AC XY: 8AN XY: 635298
GnomAD4 genome AF: 0.00000659 AC: 1AN: 151792Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74138
ClinVar
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 | Invitae | 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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at