11-121452363-G-C
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2BP4_ModerateBS1_Supporting
The NM_003105.6(SORL1):c.32G>C(p.Arg11Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000461 in 1,552,880 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.00031 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00048 ( 0 hom. )
Consequence
SORL1
NM_003105.6 missense
NM_003105.6 missense
Scores
3
3
13
Clinical Significance
Conservation
PhyloP100: 4.22
Genes affected
SORL1 (HGNC:11185): (sortilin related receptor 1) This gene encodes a mosaic protein that belongs to at least two families: the vacuolar protein sorting 10 (VPS10) domain-containing receptor family, and the low density lipoprotein receptor (LDLR) family. The encoded protein also contains fibronectin type III repeats and an epidermal growth factor repeat. The encoded preproprotein is proteolytically processed to generate the mature receptor, which likely plays roles in endocytosis and sorting. Mutations in this gene may be associated with Alzheimer's disease. [provided by RefSeq, Feb 2016]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -1 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
BP4
?
Computational evidence support a benign effect (MetaRNN=0.18536413).
BS1
?
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000309 (47/152050) while in subpopulation NFE AF= 0.000677 (46/67974). AF 95% confidence interval is 0.000521. There are 0 homozygotes in gnomad4. There are 20 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
|---|---|---|---|---|---|---|---|
| SORL1 | NM_003105.6 | c.32G>C | p.Arg11Pro | missense_variant | 1/48 | ENST00000260197.12 | |
| SORL1-AS1 | NR_183636.1 | n.293+312C>G | intron_variant, non_coding_transcript_variant |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| SORL1 | ENST00000260197.12 | c.32G>C | p.Arg11Pro | missense_variant | 1/48 | 1 | NM_003105.6 | P1 | |
| SORL1-AS1 | ENST00000501964.1 | n.339+312C>G | intron_variant, non_coding_transcript_variant | 2 | |||||
| SORL1-AS1 | ENST00000529160.1 | n.245+312C>G | intron_variant, non_coding_transcript_variant | 2 | |||||
| SORL1 | ENST00000532451.1 | upstream_gene_variant | 1 |
Frequencies
GnomAD3 genomes ? AF: 0.000309 AC: 47AN: 152050Hom.: 0 Cov.: 32
GnomAD3 genomes
?
AF:
AC:
47
AN:
152050
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:
GnomAD3 exomes AF: 0.000142 AC: 23AN: 162290Hom.: 0 AF XY: 0.000144 AC XY: 13AN XY: 90282
GnomAD3 exomes
AF:
AC:
23
AN:
162290
Hom.:
AF XY:
AC XY:
13
AN XY:
90282
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.000478 AC: 669AN: 1400830Hom.: 0 Cov.: 30 AF XY: 0.000436 AC XY: 303AN XY: 694200
GnomAD4 exome
AF:
AC:
669
AN:
1400830
Hom.:
Cov.:
30
AF XY:
AC XY:
303
AN XY:
694200
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome ? AF: 0.000309 AC: 47AN: 152050Hom.: 0 Cov.: 32 AF XY: 0.000269 AC XY: 20AN XY: 74290
GnomAD4 genome
?
AF:
AC:
47
AN:
152050
Hom.:
Cov.:
32
AF XY:
AC XY:
20
AN XY:
74290
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
Alfa
AF:
Hom.:
Bravo
AF:
TwinsUK
AF:
AC:
1
ALSPAC
AF:
AC:
4
ESP6500AA
AF:
AC:
0
ESP6500EA
AF:
AC:
6
ExAC
?
AF:
AC:
18
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not provided Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Dec 01, 2023 | This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 11 of the SORL1 protein (p.Arg11Pro). This variant is present in population databases (rs147575757, gnomAD 0.04%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with Alzheimer disease (PMID: 27249223). ClinVar contains an entry for this variant (Variation ID: 2196018). 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 tolerated. 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:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
Cadd
Uncertain
Dann
Uncertain
DEOGEN2
Benign
T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
D
LIST_S2
Benign
T
M_CAP
Pathogenic
D
MetaRNN
Benign
T
MetaSVM
Benign
T
MutationAssessor
Benign
L
MutationTaster
Benign
N
PrimateAI
Pathogenic
D
PROVEAN
Benign
N
REVEL
Uncertain
Sift
Pathogenic
D
Sift4G
Uncertain
D
Polyphen
B
Vest4
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
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