NM_001034850.3:c.457A>G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP3_Moderate

The NM_001034850.3(RETREG1):​c.457A>G​(p.Ser153Gly) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,608 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

RETREG1
NM_001034850.3 missense, splice_region

Scores

7
11
Splicing: ADA: 0.9997
2

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 3.32
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 Likely_pathogenic. Variant got 6 ACMG points.

PM1
In a modified_residue Phosphoserine (size 0) in uniprot entity RETR1_HUMAN
PM2
Very rare variant in population databases, with high coverage;
PP3
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
RETREG1NM_001034850.3 linkc.457A>G p.Ser153Gly missense_variant, splice_region_variant Exon 3 of 9 ENST00000306320.10 NP_001030022.1 Q9H6L5-1
RETREG1XM_011514053.4 linkc.457A>G p.Arg153Gly missense_variant, splice_region_variant Exon 3 of 10 XP_011512355.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
RETREG1ENST00000306320.10 linkc.457A>G p.Ser153Gly missense_variant, splice_region_variant Exon 3 of 9 1 NM_001034850.3 ENSP00000304642.9 Q9H6L5-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461608
Hom.:
0
Cov.:
31
AF XY:
0.00000138
AC XY:
1
AN XY:
727094
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:
8.99e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Uncertain:2
Aug 28, 2024
GeneDx
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on splicing; In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Mar 01, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces serine, which is neutral and polar, with glycine, which is neutral and non-polar, at codon 153 of the RETREG1 protein (p.Ser153Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of hereditary sensory and autonomic neuropathy (Invitae). ClinVar contains an entry for this variant (Variation ID: 538132). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.16
BayesDel_addAF
Benign
-0.17
T
BayesDel_noAF
Benign
-0.49
CADD
Pathogenic
26
DANN
Uncertain
1.0
DEOGEN2
Benign
0.13
T
Eigen
Uncertain
0.28
Eigen_PC
Uncertain
0.33
FATHMM_MKL
Uncertain
0.91
D
LIST_S2
Benign
0.65
T
M_CAP
Benign
0.022
T
MetaRNN
Benign
0.25
T
MetaSVM
Benign
-1.0
T
PrimateAI
Uncertain
0.58
T
PROVEAN
Benign
-1.4
N
REVEL
Benign
0.11
Sift
Uncertain
0.0060
D
Sift4G
Uncertain
0.035
D
Polyphen
0.83
P
Vest4
0.28
MutPred
0.30
Gain of sheet (P = 0.0266);
MVP
0.50
MPC
0.67
ClinPred
0.91
D
GERP RS
5.0
Varity_R
0.32
gMVP
0.27

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
0.98
SpliceAI score (max)
0.64
Details are displayed if max score is > 0.2
DS_DL_spliceai
0.64
Position offset: -1

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: rs1554022467; hg19: chr5-16565873; API