10-104641525-C-G

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_014978.3(SORCS3):c.198C>G(p.Ser66Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000176 in 1,474,546 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000019 ( 0 hom. )

Consequence

SORCS3
NM_014978.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.39

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

complex neurodevelopmental disorder
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

SORCS3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.10229662).

BS2

High AC in GnomAdExome4 at 25 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SORCS3	NM_014978.3 link	c.198C>G	p.Ser66Arg	missense_variant	Exon 1 of 27	ENST00000369701.8	NP_055793.1	Q9UPU3Q86XB2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SORCS3	ENST00000369701.8 link	c.198C>G	p.Ser66Arg	missense_variant	Exon 1 of 27	1	NM_014978.3	ENSP00000358715.3		Q9UPU3

Frequencies

GnomAD3 genomes

AF:

0.00000660

AC:

AN:

151472

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000208

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000673

AC:

AN:

74274

AF XY:

0.000117

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000168

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000734

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000189

AC:

AN:

1323074

Hom.:

Cov.:

AF XY:

0.0000261

AC XY:

AN XY:

651664

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26514

American (AMR)

AF:

0.00

AC:

AN:

26346

Ashkenazi Jewish (ASJ)

AF:

0.0000869

AC:

AN:

23026

East Asian (EAS)

AF:

0.00

AC:

AN:

28954

South Asian (SAS)

AF:

0.000110

AC:

AN:

72440

European-Finnish (FIN)

AF:

0.00

AC:

AN:

32768

Middle Eastern (MID)

AF:

0.000248

AC:

AN:

4030

European-Non Finnish (NFE)

AF:

0.00000854

AC:

AN:

1054048

Other (OTH)

AF:

0.0000910

AC:

AN:

54948

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.519

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00000660

AC:

AN:

151472

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

73990

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41210

American (AMR)

AF:

0.00

AC:

AN:

15238

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5098

South Asian (SAS)

AF:

0.000208

AC:

AN:

4798

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10522

Middle Eastern (MID)

AF:

0.00

AC:

AN:

308

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67842

Other (OTH)

AF:

0.00

AC:

AN:

2080

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.0000384

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Sep 03, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.198C>G (p.S66R) 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 198, causing the serine (S) at amino acid position 66 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

0.14

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.51

CADD

Benign

(source)

DANN

Benign

0.92

DEOGEN2

Benign

0.011

T;T

Eigen

Benign

-0.39

Eigen_PC

Benign

-0.26

FATHMM_MKL

Benign

0.48

LIST_S2

Benign

0.48

.;T

M_CAP

Benign

0.046

MetaRNN

Benign

0.10

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

N;N

PhyloP100

1.4

PrimateAI

Pathogenic

0.85

PROVEAN

Benign

0.10

N;.

REVEL

Benign

0.057

Sift

Benign

0.14

T;.

Sift4G

Benign

0.70

T;T

Polyphen

0.23

B;B

Vest4

0.31

MutPred

0.34

Gain of MoRF binding (P = 0.0101);Gain of MoRF binding (P = 0.0101);

MVP

0.53

MPC

0.38

ClinPred

0.023

GERP RS

3.6

PromoterAI

-0.014

Neutral

(source)

Varity_R

0.14

gMVP

0.28

Mutation Taster

=83/17

polymorphism

(source)

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

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10-104641525-C-G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over