10-104641718-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_014978.3(SORCS3):ā€‹c.391A>Cā€‹(p.Ser131Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00011 in 1,541,772 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: š‘“ 0.000079 ( 0 hom., cov: 32)
Exomes š‘“: 0.00011 ( 0 hom. )

Consequence

SORCS3
NM_014978.3 missense

Scores

3
16

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.465
Variant links:
Genes affected
SORCS3 (HGNC:16699): (sortilin related VPS10 domain containing receptor 3) This gene encodes a type-I receptor transmembrane protein that is a member of the vacuolar protein sorting 10 receptor family. Proteins of this family are defined by a vacuolar protein sorting 10 domain at the N-terminus. The N-terminal segment of this domain has a consensus motif for proprotein convertase processing, and the C-terminal segment of this domain is characterized by ten conserved cysteine residues. The vacuolar protein sorting 10 domain is followed by a leucine-rich segment, a transmembrane domain, and a short C-terminal cytoplasmic domain that interacts with adaptor molecules. The transcript is expressed at high levels in the brain, and candidate gene studies suggest that genetic variation in this gene is associated with Alzheimer's disease. Consistent with this observation, knockdown of the gene in cell culture results in an increase in amyloid precursor protein processing. [provided by RefSeq, Dec 2014]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.07403618).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
SORCS3NM_014978.3 linkuse as main transcriptc.391A>C p.Ser131Arg missense_variant 1/27 ENST00000369701.8 NP_055793.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
SORCS3ENST00000369701.8 linkuse as main transcriptc.391A>C p.Ser131Arg missense_variant 1/271 NM_014978.3 ENSP00000358715 P1

Frequencies

GnomAD3 genomes
AF:
0.0000789
AC:
12
AN:
152006
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000725
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000132
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000679
AC:
9
AN:
132528
Hom.:
0
AF XY:
0.0000416
AC XY:
3
AN XY:
72192
show subpopulations
Gnomad AFR exome
AF:
0.000168
Gnomad AMR exome
AF:
0.0000832
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000129
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000114
AC:
158
AN:
1389656
Hom.:
0
Cov.:
33
AF XY:
0.000121
AC XY:
83
AN XY:
685288
show subpopulations
Gnomad4 AFR exome
AF:
0.0000320
Gnomad4 AMR exome
AF:
0.0000566
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000381
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000139
Gnomad4 OTH exome
AF:
0.0000347
GnomAD4 genome
AF:
0.0000789
AC:
12
AN:
152116
Hom.:
0
Cov.:
32
AF XY:
0.0000807
AC XY:
6
AN XY:
74358
show subpopulations
Gnomad4 AFR
AF:
0.0000723
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000132
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000120
Hom.:
0
Bravo
AF:
0.0000642
ExAC
AF:
0.0000175
AC:
1

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsApr 24, 2024The c.391A>C (p.S131R) alteration is located in exon 1 (coding exon 1) of the SORCS3 gene. This alteration results from a A to C substitution at nucleotide position 391, causing the serine (S) at amino acid position 131 to be replaced by an arginine (R). 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
0.24
BayesDel_addAF
Benign
-0.46
T
BayesDel_noAF
Benign
-0.64
CADD
Benign
19
DANN
Uncertain
0.98
DEOGEN2
Benign
0.012
T;T
Eigen
Benign
-0.39
Eigen_PC
Benign
-0.22
FATHMM_MKL
Uncertain
0.76
D
LIST_S2
Benign
0.45
.;T
M_CAP
Benign
0.024
T
MetaRNN
Benign
0.074
T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
0.0
N;N
MutationTaster
Benign
0.82
N
PrimateAI
Uncertain
0.75
T
PROVEAN
Benign
-0.38
N;.
REVEL
Benign
0.082
Sift
Benign
0.13
T;.
Sift4G
Benign
0.41
T;T
Polyphen
0.0
B;B
Vest4
0.10
MutPred
0.30
Loss of phosphorylation at S131 (P = 0.0013);Loss of phosphorylation at S131 (P = 0.0013);
MVP
0.33
MPC
0.38
ClinPred
0.043
T
GERP RS
4.0
Varity_R
0.15
gMVP
0.43

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: rs776587267; hg19: chr10-106401476; API