Variant 10-104641882-C-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_014978.3(SORCS3):c.555C>A(p.Ser185Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

SORCS3
NM_014978.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.524

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]

SORCS3 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SORCS3	NM_014978.3 linkuse as main transcript	c.555C>A	p.Ser185Arg	missense_variant	1/27	ENST00000369701.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SORCS3	ENST00000369701.8 linkuse as main transcript	c.555C>A	p.Ser185Arg	missense_variant	1/27	1	NM_014978.3	P1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

6.95e-7

AC:

AN:

1438852

Hom.:

Cov.:

AF XY:

0.00000140

AC XY:

AN XY:

714584

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:

9.05e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

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 submitter

clinical testing

Ambry Genetics

Feb 14, 2023

The c.555C>A (p.S185R) alteration is located in exon 1 (coding exon 1) of the SORCS3 gene. This alteration results from a C to A substitution at nucleotide position 555, causing the serine (S) at amino acid position 185 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

Pathogenic

0.94

BayesDel_addAF

Uncertain

0.10

BayesDel_noAF

Benign

-0.090

Cadd

Benign

Dann

Uncertain

0.99

DEOGEN2

Benign

0.037

T;T

Eigen

Benign

-0.19

Eigen_PC

Benign

-0.13

FATHMM_MKL

Uncertain

0.87

M_CAP

Benign

0.021

MetaRNN

Uncertain

0.45

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.1

M;M

MutationTaster

Benign

0.78

PrimateAI

Uncertain

0.77

PROVEAN

Benign

-1.9

N;.

REVEL

Benign

0.13

Sift

Uncertain

0.0010

D;.

Sift4G

Benign

0.063

T;T

Polyphen

0.34

B;B

Vest4

0.67

MutPred

0.27

Loss of glycosylation at S185 (P = 0.0158);Loss of glycosylation at S185 (P = 0.0158);

MVP

0.43

MPC

0.63

ClinPred

0.79

GERP RS

1.4

Varity_R

0.31

gMVP

0.71

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over