10-104641386-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_014978.3(SORCS3):​c.59C>G​(p.Thr20Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Consequence

SORCS3
NM_014978.3 missense

Scores

2
2
15

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.02
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.28145975).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
SORCS3NM_014978.3 linkuse as main transcriptc.59C>G p.Thr20Arg 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.59C>G p.Thr20Arg missense_variant 1/271 NM_014978.3 ENSP00000358715 P1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
32

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 GeneticsMar 11, 2024The c.59C>G (p.T20R) alteration is located in exon 1 (coding exon 1) of the SORCS3 gene. This alteration results from a C to G substitution at nucleotide position 59, causing the threonine (T) at amino acid position 20 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
0.13
BayesDel_addAF
Benign
-0.14
T
BayesDel_noAF
Benign
-0.44
CADD
Benign
23
DANN
Uncertain
0.99
DEOGEN2
Benign
0.014
T;T
Eigen
Benign
0.0030
Eigen_PC
Benign
-0.0050
FATHMM_MKL
Benign
0.45
N
LIST_S2
Benign
0.53
.;T
M_CAP
Uncertain
0.27
D
MetaRNN
Benign
0.28
T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
0.0
N;N
MutationTaster
Benign
0.85
N
PrimateAI
Pathogenic
0.93
D
PROVEAN
Benign
-0.36
N;.
REVEL
Benign
0.054
Sift
Pathogenic
0.0
D;.
Sift4G
Benign
0.53
T;T
Polyphen
0.91
P;P
Vest4
0.26
MutPred
0.39
Gain of MoRF binding (P = 0.02);Gain of MoRF binding (P = 0.02);
MVP
0.60
MPC
1.1
ClinPred
0.61
D
GERP RS
3.2
Varity_R
0.29
gMVP
0.52

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr10-106401144; API