11-121452446-A-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_003105.6(SORL1):ā€‹c.115A>Gā€‹(p.Ser39Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000267 in 1,498,448 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: š‘“ 0.0000066 ( 0 hom., cov: 32)
Exomes š‘“: 0.0000022 ( 0 hom. )

Consequence

SORL1
NM_003105.6 missense

Scores

2
17

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.370
Variant links:
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]
SORL1-AS1 (HGNC:55594): (SORL1 antisense RNA 1)

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.067596614).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SORL1NM_003105.6 linkc.115A>G p.Ser39Gly missense_variant Exon 1 of 48 ENST00000260197.12 NP_003096.2 Q92673A0A024R3H2
SORL1-AS1NR_183636.1 linkn.293+229T>C intron_variant Intron 1 of 2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SORL1ENST00000260197.12 linkc.115A>G p.Ser39Gly missense_variant Exon 1 of 48 1 NM_003105.6 ENSP00000260197.6 Q92673
SORL1ENST00000532451.1 linkn.67A>G non_coding_transcript_exon_variant Exon 1 of 15 1
SORL1-AS1ENST00000501964.1 linkn.339+229T>C intron_variant Intron 1 of 1 2
SORL1-AS1ENST00000529160.1 linkn.245+229T>C intron_variant Intron 1 of 1 2

Frequencies

GnomAD3 genomes
AF:
0.00000658
AC:
1
AN:
151868
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.000288
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000214
AC:
2
AN:
93444
Hom.:
0
AF XY:
0.0000385
AC XY:
2
AN XY:
51952
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.000336
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000223
AC:
3
AN:
1346580
Hom.:
0
Cov.:
31
AF XY:
0.00000453
AC XY:
3
AN XY:
662376
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.0000863
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.0000179
GnomAD4 genome
AF:
0.00000658
AC:
1
AN:
151868
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74182
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.000288
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000937
Hom.:
0
Bravo
AF:
0.00000378
ExAC
AF:
0.0000219
AC:
2

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Apr 20, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.115A>G (p.S39G) alteration is located in exon 1 (coding exon 1) of the SORL1 gene. This alteration results from a A to G substitution at nucleotide position 115, causing the serine (S) at amino acid position 39 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.052
BayesDel_addAF
Benign
-0.095
T
BayesDel_noAF
Benign
-0.37
CADD
Benign
18
DANN
Benign
0.94
DEOGEN2
Benign
0.075
T
Eigen
Benign
-0.83
Eigen_PC
Benign
-0.69
FATHMM_MKL
Benign
0.12
N
LIST_S2
Benign
0.53
T
M_CAP
Pathogenic
0.43
D
MetaRNN
Benign
0.068
T
MetaSVM
Benign
-0.67
T
MutationAssessor
Benign
0.69
N
PrimateAI
Pathogenic
0.86
D
PROVEAN
Benign
-1.1
N
REVEL
Benign
0.25
Sift
Benign
0.45
T
Sift4G
Benign
0.55
T
Polyphen
0.0
B
Vest4
0.16
MutPred
0.18
Loss of disorder (P = 0.2233);
MVP
0.51
MPC
0.23
ClinPred
0.059
T
GERP RS
-0.55
Varity_R
0.10
gMVP
0.28

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
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: rs771624504; hg19: chr11-121323155; API